Approach

The management of clinically non-functioning pituitary adenomas (CNFPAs) includes surgical resection, radiotherapy, medical therapy, or observation (active surveillance).[53][54]​​​

The goals of therapy for CNFPAs with mass effect are to remove the tumour as completely as feasible, reverse any visual or other neurological deficit, reverse any hormonal deficit, and preserve the function of the unaffected pituitary gland.[54]​

Observation alone is indicated for clinically non-functional pituitary micro-adenomas and macro-adenomas without mass effect and not abutting optic chiasm.[55][56]​​​​

General approach

Therapy is directed by:

  • the size of the tumour,

  • presence of parasellar extension including compression of the optic pathway and/or invasion of cavernous sinuses and sphenoid sinus,

  • complications such as pituitary apoplexy, and

  • experience of the neurosurgeon.

Multidisciplinary clinical care involving endocrinologists, neuroradiologists, neurosurgeons, and radiation oncologists is preferred.

Management of pituitary apoplexy

Pituitary apoplexy is a potentially life-threatening condition because it may be associated with acute adrenal insufficiency.[12]​​ Prompt recognition of the condition should be followed by administration of parenteral corticosteroids along with intravenous fluids and parenteral analgesia. If left untreated it may be fatal. Surgical intervention, preferably within 24 to 48 hours of onset, is generally recommended in cases with progressive vision loss or cranial neuropathy, to minimise the risk of permanent neurological deficit.

Observation

Micro-adenomas generally do not grow and if they do, they usually do not impair visual fields or cause hypopituitarism. In one study, among 166 patients with micro-adenomas, 17 (10.2%) showed a 10% increase in tumour size (3%-40%) over a mean follow-up of 4.3 years. The majority (80%) remained unchanged, while 10% demonstrated a reduction in tumour size.[57] For patients with clinically non-functional pituitary micro-adenomas, MRI may be repeated after 1 year initially, with further MRI studies only if the patient develops symptoms suggestive of mass effect.[57]

Macro-adenomas have a propensity to grow: among 356 macro-adenomas, 87 (24%) increased in size, 45 (13%) decreased, and 224 (63%) remained unchanged over a mean follow-up of 4.3 years.[57] For patients with clinically non-functional pituitary macro-adenomas, an appropriate schedule would be to repeat the MRI in 6 months, then yearly for 5 years, followed by every 2 to 3 years if stable. Surgery is indicated if there is tumour growth. One paper reported that 20% of patients with non-functioning-macroadenomas on active surveillance may require further intervention during a follow-up period of 7 years.[58]

Surgery

Trans-sphenoidal surgery (TSS) is indicated as first-line therapy for patients with symptomatic CNFPAs, including:[6][53]​​

  • Pituitary apoplexy

  • Clinically non-functional pituitary macro-adenomas that abut the optic chiasm, and those with mass effect such as visual field defect

  • Other neurological deficits related to compression from the tumour

  • Tumours that demonstrate progressive increase in size

  • Most pituitary macroadenomas, with consideration of size at presentation and likelihood for growth and clinical impact if growth occurs.

  • Refractory headaches not attributable to other headache syndromes

  • Endocrine dysfunction related to compression from the tumour, including hypopituitarism or stalk effect causing hyperprolactinaemia.

Surgery may be indicated when the diagnosis is in doubt, in order to confirm the diagnosis. The availability of an experienced neurosurgeon has been shown to improve surgical outcome.[6]​​

TSS is carried out with the use of minimally invasive techniques and computer-guided neuro-navigational devices. The pituitary is approached via either a transnasal submucosal or sublabial incision. Intra-operative MRI scanning , if available, may improve surgical outcomes. Both microscopic and endoscopic TSS approaches are effective for non-functioning pituitary adenomas. An endoscopic approach potentially provides improved visualisation of the surgical field compared with a traditional microscope-based trans-sphenoidal approach. However there is no convincing proof of superiority from existing studies.[54] More large, prospective, randomised studies are required to compare the two techniques.[59]

With TSS, hormone deficits are resolved in 15% to 50% of patients, and hyperprolactinaemia resolves in more than two-thirds of patients.[6]​ Surgery may induce a new hormone deficit in 2% to 15% of patients.[6]​ Transient diabetes insipidus (DI) may occur in up to one third of cases, but the risk of permanent DI is only 3% to 4%.[54]​ Mortality risk is about 0.2%.[6]​ Postoperative tumour recurrence varies from 15% to 66% in those treated with surgery alone.[60]​ Following TSS, visual field defects are improved or normalised in over 75% of cases.[61]​​ Improvement of visual function may even continue after surgical treatment in some patients.[61]

Assessment of the efficacy of surgery is recommended at 3 to 4 months following surgery, by which time postoperative changes have typically resolved.[62]

Craniotomy is reserved for tumours with large intracranial components particularly affecting the frontal (sub-frontal approach) or temporal (pterional approach) lobes.

There are several studies that conclude that incidental pituitary neuroendocrine tumours that require surgery have a better prognosis than symptomatic tumours.[63]​ Furthermore, one study found that the surgical outcome for completely asymptomatic incidentalomas was better than for symptomatic ones (defined as hormonal or visual deficit on testing). While the study did not advocate surgical removal of all asymptomatic incidental CNFPAs, the data suggest that when surgery is indicated the outcome may be more favourable in asymptomatic patients with CNFPAs.[64]

Radiotherapy

Radiotherapy is typically used postoperatively when there is significant residual tumour mass, particularly tumour invading the cavernous sinus, or to treat a recurrence.[6][53]​​​ It may be used for tumour growth control if surgery is not an option.[6]

There are two forms of radiotherapy that may be used:

  • Conventional radiotherapy

  • Stereotactic radiosurgery.

Conventional radiotherapy may be associated with substantial delayed complications:[65]

  • Hypopituitarism occurs in 30% to 60% of patients 5 to 10 years after irradiation.

  • There is a 4-fold increased risk of stroke and a the cumulative increased risk of secondary brain tumours is 2% at 10 years.

  • There may be an increased risk of late cognitive dysfunction and an up to 6% risk of radiation-induced optic neuropathy.

The risk of hypopituitarism depends on the delivered dose, with doses >20 Gy causing detectable deficits in anterior pituitary function as well as hyperprolactinaemia. The time to onset of hormone deficit is shorter with higher doses. Other risk factors for developing hypopituitarism include a large residual volume of tumour before radiation, prior surgical resection, and pre-existing pituitary deficiency.[66]

Stereotactic radiosurgery is applied using photons: gamma knife (GK), cyberknife (CK), and linear accelerator (LINAC); or using proton-beam radiation therapy.[67] Protons have a dosimetric advantage over photons, particularly in the case of larger intra-cranial lesions; however, for smaller lesions, GK, CK, and LINAC appeared to be equally effective.​[68] ​With stereotactic radiosurgery the goal is to deliver a high radiation dose to a more defined target while minimising damage to surrounding tissues. The surgery aspect relates to the use of invasive fixating frames to immobilise the patient. MRI and CT scanning are used to define tumour anatomy and map out the radiation field. A single dose of radiation is delivered either via multiple cobalt beams (GK) or a linear accelerator (LINAC). CK is a mobile linear accelerator mounted on a robotic arm with an image-guided robotic system.[65] With stereotactic radiosurgery, single doses of 8 to 10 Gy are given to tumours 5 mm or more from the optic apparatus to avoid optic neuropathy. Tumour control with stereotactic radiosurgery is estimated at about 90% to 100% at 5 years.[65]​ The 5-year incidence of hypopituitarism is between 10% to 40%.[65]​ Radiation-induced optic neuropathy and cranial nerve radiation damage have been reported at <3% and <7% respectively.[65]

Hormonal treatment

CNFPAs may be associated with hypopituitarism resulting in central adrenal insufficiency, hypothyroidism, hypogonadism, and growth hormone deficiency. Hormone replacement may be necessary based on biochemical work-up and clinical presentation.[69]​​ Replacement hormones include thyroid hormone, glucocorticoids, oestrogen or androgen, and growth hormone (somatropin). Women with an intact uterus receiving daily oestrogen should take progesterone to prevent cystic hyperplasia of the endometrium and possible transformation to cancer.

A study that evaluated the long-term mortality effect of low-, medium-, and high-dose glucocorticoid replacement regimens in patients with CNFPAs and secondary adrenal insufficiency found higher glucocorticoid replacement doses were associated with increased overall mortality. The study further substantiates the importance of a balanced and adjusted glucocorticoid replacement therapy in patients with CNFPAs and insufficiency of hypothalamic-pituitary-adrenal (HPA) axis.[70] It is important to use replacement treatment that results in a physiological cortisol exposure to prevent increased mortality.​[71]

Medical therapy

Medical therapy may be used as a second-line treatment for patients with CNFPAs with residual or recurrent disease following initial therapy with TSS and radiotherapy. However, unlike functioning pituitary adenomas in which hormone levels can be measured, the only true indicator of a response in CNFPAs is a reduction in tumour size.[37]

CNFPAs express dopamine and somatostatin receptors on their cell membranes, and addition of dopamine agonists to tumour cell cultures of gonadotroph origin suppresses the release and synthesis of gonadotrophins and gonadotrophin subunits.[72]​​ Compared with somatostatin analogues, dopamine agonists are more effective in reducing tumour volume.[37][73]

Dopamine agonists (e.g., bromocriptine, cabergoline) have been used in small studies with mixed results.[73] However, their use in CNFPAs remains controversial, as the evidence is limited.​[74] Trials using cabergoline, a potent specific dopamine D2 receptor agonist, in CNFPAs appear to be the most promising in inducing tumour shrinkage and preventing tumour growth​.[73][75][76]

High-dose cabergoline (>3 mg a day) has been associated with significant cardiac valvular disease among patients with Parkinson's disease.​​​​​[77] Most studies do not show any evidence of valvular heart disease at lower doses that are typically used to treat patients with prolactinomas.​[78] Use of cabergoline in CNFPAs does not appear to result in valvular changes.​[75]

Combination therapy (somatostatin analogue plus dopamine agonist) has been proposed, but clinical data is very limited in patients with CNFPAs.[73]

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