Approach

The management of clinically nonfunctioning pituitary adenomas (CNFPAs) includes surgical resection, radiation therapy, medical therapy, or observation (active surveillance).[54][55]​​​

The goals of therapy for CNFPAs with mass effect are to remove the tumor as completely as feasible, reverse any visual or other neurologic deficit, reverse any hormonal deficit, and preserve the function of the unaffected pituitary gland.[55]​

Observation alone is indicated for clinically nonfunctional pituitary microadenomas and macroadenomas without mass effect and not abutting optic chiasm.[53][56]​​​​

General approach

Therapy is directed by:

  • the size of the tumor,

  • 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 minimize the risk of permanent neurologic deficit. 

Observation

Microadenomas 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 microadenomas, 17 (10.2%) showed a 10% increase in tumor size (3%-40%) over a mean follow-up of 4.3 years. The majority (80%) remained unchanged, while 10% demonstrated a reduction in tumor size.[57] For patients with clinically nonfunctional pituitary microadenomas, MRI may be repeated after 1 year initially, with further MRI studies only if the patient develops symptoms suggestive of mass effect.[57]

Macroadenomas have a propensity to grow: among 356 macroadenomas, 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 nonfunctional pituitary macroadenomas, 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 tumor growth. One paper reported that 20% of patients with nonfunctioning-macroadenomas on active surveillance may require further intervention during a follow-up period of 7 years.[58]

Surgery

Transsphenoidal surgery (TSS) is indicated as first-line therapy for patients with symptomatic CNFPAs, including:[6][54]​​

  • Pituitary apoplexy

  • Clinically nonfunctional pituitary macroadenomas that abut the optic chiasm, and those with mass effect such as visual field defect

  • Other neurologic deficits related to compression from the tumor

  • Tumors 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 tumor, including hypopituitarism or stalk effect causing hyperprolactinemia.

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. Intraoperative MRI scanning , if available, may improve surgical outcomes. Both microscopic and endoscopic TSS approaches are effective for nonfunctioning pituitary adenomas. An endoscopic approach potentially provides improved visualization of the surgical field compared with a traditional microscope-based transsphenoidal approach. However there is no convincing proof of superiority from existing studies.[55] More​ large, prospective, randomized studies are required to compare the two techniques.[59]

With TSS, hormone deficits are resolved in 15% to 50% of patients, and hyperprolactinemia 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%.[55]​ Mortality risk is about 0.2%.[6]​ Postoperative tumor recurrence varies from 15% to 66% in those treated with surgery alone.[60]​ Following TSS, visual field defects are improved or normalized 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 tumors with large intracranial components particularly affecting the frontal (subfrontal approach) or temporal (pterional approach) lobes.

There are several studies that conclude that incidental pituitary neuroendocrine tumors that require surgery have a better prognosis than symptomatic tumors.[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 favorable in asymptomatic patients with CNFPAs.[64]

Radiation therapy

Radiation therapy is typically used postoperatively when there is significant residual tumor mass, particularly tumor invading the cavernous sinus, or to treat a recurrence.[6][54]​​​ It may be used for tumor growth control if surgery is not an option.[6]

There are two forms of radiation therapy that may be used:

  • Conventional radiation therapy

  • Stereotactic radiosurgery.

Conventional radiation therapy 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 tumors 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 hyperprolactinemia. The time to onset of hormone deficit is shorter with higher doses. Other risk factors for developing hypopituitarism include a large residual volume of tumor before radiation, prior surgical resection, and preexisting pituitary deficiency.[66]

Stereotactic radiosurgery is applied using photons: gamma knife (GK), cyberknife (CK), and linear accelerator (LINAC); or using proton-beam radiotherapy.[67] Protons have a dosimetric advantage over photons, particularly in the case of larger intracranial 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 minimizing damage to surrounding tissues. The surgery aspect relates to the use of invasive fixating frames to immobilize the patient. MRI and CT scanning are used to define tumor 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 tumors 5 mm or more from the optic apparatus to avoid optic neuropathy. Tumor 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 workup and clinical presentation.[69]​​ Replacement hormones include thyroid hormone, glucocorticoids, estrogen or androgen, and growth hormone (somatropin). Women with an intact uterus receiving daily estrogen 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 physiologic 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 radiation therapy. 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 tumor size.[37]

CNFPAs express dopamine and somatostatin receptors on their cell membranes, and addition of dopamine agonists to tumor cell cultures of gonadotroph origin suppresses the release and synthesis of gonadotropins and gonadotropin subunits.[72]​​ Compared with somatostatin analogs, dopamine agonists are more effective in reducing tumor 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 tumor shrinkage and preventing tumor growth.[73][75][76]​​​​​​

High-dose cabergoline (>3 mg a day) has been associated with significant cardiac valvular disease among patients with Parkinson 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 analog plus dopamine agonist) has been proposed, but clinical data is very limited in patients with CNFPAs.[73]

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