Pituitary Macroadenomas

Author: James R Mulinda, MD, FACP, FACE; Chief Editor: George T Griffing, MD Updated: Jun 14, 2013

Background
The sellar region is a site of various types of tumors. Pituitary adenomas are the most common. They arise from epithelial pituitary cells and account for 10-15% of all intracranial tumors. Tumors exceeding 10 mm are defined as macroadenomas, and those smaller than 10 mm are termed microadenomas. Most pituitary adenomas are microadenomas.

Recent studies
In a prospective, randomized study, Mao et al investigated whether treatment with lanreotide prior to transsphenoidal surgery for macroadenomas would improve cure rates in patients with newly diagnosed acromegaly. The study included 49 patients who were administered 4 months of preoperative lanreotide treatment and 49 patients who underwent transsphenoidal surgery without pretreatment. The authors reported a 49% cure rate (24 patients) in the pretreatment group following surgery and an 18.4% cure rate (9 patients) in the nonlanreotide group. Mao et al concluded that in patients with growth hormone secreting pituitary adenomas, preoperative lanreotide treatment increases cure rates from transsphenoidal surgery.[1] In another study, Han et al compared the 1-nostril and 2-nostril approaches with transsphenoidal surgery. The researchers concluded that the 1-nostril method is fast, minimally invasive, and adequate for resection of most pituitary adenomas.[2] Adenomas with a dumbbell configuration have been difficult to excise with transsphenoidal surgery. Sankhla et al presented their experience with the extended endoscopic endonasal approach (EEEA), concluding that it is a potentially viable option but additional study is needed.[3]

Pathophysiology
Pituitary macroadenomas are benign epithelial neoplasms composed of adenohypophysial cells. Primary malignant tumors of the pituitary are extremely rare. Evidence suggests that pituitary adenoma development occurs in several steps, including an irreversible initiation phase followed by tumor promotion. Pituitary tumor development is a monoclonal process with several contributing factors. Causal contributors include heredity and hormonal influence and genetic mutations. The monoclonal nature of most pituitary tumors suggests that they arise from a mutated pituitary cell. However, the exact pathophysiologic/molecular mechanisms leading to the development of pituitary adenomas remain unknown. The role of genetic mutations was highlighted in a report suggesting that patients with pituitary tumors from 4 Irish families share a common mutation with a patient from the 18th century who had pituitary tumormediated gigantism.[4] Some pituitary tumors may occur as part of a clinical syndrome. In multiple endocrine neoplasia type 1 (MEN 1), an autosomal dominant genetic disorder, pituitary adenomas (most often prolactinomas) occur in association with tumors of the parathyroid and pancreatic islet cells. In McCune-Albright syndrome, skin lesions and polyostotic fibrous dysplasia occur with hyperfunctioning endocrinopathies. This syndrome results from an activating mutation (somatic mutation) of the alpha subunit of the Gs protein and involves tissues whose response to hormonal signals is mediated by adenylate cyclase. The most common pituitary tumor in McCune-Albright syndrome is somatotropinoma, resulting in acromegaly. Interestingly, a significant proportion of somatotropinomas in sporadic cases of acromegaly harbor the same mutations. Carney complex is an autosomal dominant disorder characterized by primary pigmented nodular adrenal disease, cutaneous pigmented lesions (lentigines, blue nevi), Sertoli cell tumors of the testes, acromegaly, melanocytic schwannomas, and cardiac myxomas.

Epidemiology
Frequency
United States Pituitary tumors are found on autopsy in as many as 25% of unselected cases. The annual incidence of pituitary neoplasms varies from 1-7 cases per 100,000 population based on neurosurgical series.

Mortality/Morbidity
Morbidity in pituitary macroadenomas varies from incidentally discovered nonfunctioning tumors to disabling macroadenomas. Morbidity results from mass effects (eg, bitemporal hemianopsia), hormonal imbalance (pituitary hormone deficiency due to compression of the normal pituicytes or hormonal excess from the tumor), and patient comorbidities. Significant morbidity is also associated with treatment of these tumors.

Race
No racial predilection exists for pituitary macroadenomas.

Sex
Autopsy series show an equal distribution of pituitary tumors between men and women. Corticotropinomas are an exception, occurring mainly in women, with a female-to-male ratio of 4:1. In general, women of childbearing age are diagnosed more frequently with pituitary adenomas than men. The reason for this higher rate of diagnosis is unclear but might be related to the clinical presentation of such patients. Amenorrhea (or menstrual irregularities), which is a relatively common symptom in women with macroadenomas, raises the suspicion of a pituitary lesion.

Age
Tumors affect individuals of all ages, but incidence increases with age, peaking between the third and sixth decades of life.

History
Patients with pituitary macroadenomas may be asymptomatic or may present with complaints due to hormonal imbalance or mass effects. Tumors in asymptomatic patients may be discovered when imaging the head for unrelated medical conditions. The frequency of diagnosis of pituitary tumors has increased with widespread use of computed tomography (CT) and magnetic resonance imaging (MRI) scans. Pituitary hormone effects depend on the hormones involved. Panhypopituitarism may present with a deficiency of all the pituitary hormones, but often some are spared. The larger the tumor, the more likely it is to involve most hormones. Anterior pituitary cells are not equally sensitive to mass effects. The most sensitive are the somatotrophs and the gonadotrophs, whereas corticotrophs and thyrotrophs tend to be more resistant. Distinct clinical syndromes, specifically the following, are the result of the hormonal activity of the tumor: Hyperprolactinemia presents with hypogonadism, infertility, amenorrhea, and galactorrhea. Hyperprolactinemia can be due to increased hormone production by a prolactinoma, or it can be the result of stalk compression by the macroadenoma regardless of hormone activity. In this regard, it is a very common sequela of a pituitary macroadenoma. Corticotropin excess presents with Cushing disease. Corticotropinomas are rarely macroadenomas. Corticotropin suppression due to compression of the normal corticotrophs presents with glucocorticoid insufficiency. The clinical picture of secondary glucocorticoid deficiency is much milder than primary adrenal insufficiency, where combined mineralocorticoid and glucocorticoid deficiency occur. Thyrotropin excess presents with secondary hyperthyroidism. Thyrotropinomas are very rare tumors. They present most frequently as macroadenomas. Whether thyrotropinomas are naturally aggressive or whether the aggressive and invasive behavior is the result of delayed diagnosis is unclear. Biologically inadequate thyrotropin presents with secondary hypothyroidism. Excess growth hormone presents with acromegaly as the result of a somatotropinoma (often a

macroadenoma), while inadequate growth hormone presents with failure to thrive in children but often no complaints in adults. Gonadotropinomas most often are asymptomatic and usually secrete inactive follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-like glycoproteins and/or alpha subunit. They often are macroadenomas and usually result in hypopituitarism. Rarely, they can lead to testicular enlargement in men and ovarian hyperstimulation in women. Deficiency of gonadotropins presents with hypogonadism and infertility. Mass effects of the macroadenoma may present with visual deficits, headache, elevated intracranial pressure, or intracranial hemorrhage. Pituitary apoplexy results from infarction of a pituitary tumor or sudden hemorrhage within. This presents as a medical emergency with a headache, sudden collapse, shock, and death if not treated emergently. This tends to occur in macroadenomas. Administration of stimulatory agents, such as thyroid-stimulating hormone TSH, gonadotropin-releasing hormone (GnRH), and insulinhypoglycemia, have been postulated to lead to increased metabolic needs by the macroadenoma (which has deficient blood supply), leading to necrosis. In this context, apoplexy may be the presenting symptom of a gonadotropinoma in an elderly men receiving GnRH agonist therapy for prostate cancer. Nelson syndrome results from treatment of Cushing disease with bilateral adrenalectomy. The lack of negative glucocorticoid feedback is postulated to lead to excessive tumor growth. Such tumors are much more aggressive and locally invasive compared to the usual corticotroph adenomas.

Physical
Most patients do not have physical findings associated with macroadenomas. Physical findings may be attributable to the mass effects or hormonal disruption. When the tumor extends onto the optic chiasm, visual field deficits may be demonstrable. Sudden increase in tumor size, such as can occur with hemorrhage, may lead to elevated intracranial pressure. Hormonally active tumors might present with symptoms due to target organ stimulation, such as hyperthyroidism, Cushing syndrome, or hyperprolactinemia.

Causes
The cause of pituitary macroadenomas is unknown. The most favored theory attributes monoclonal neoplastic transformation of pituitary cells as the cause of tumor initiation and growth. The monoclonal nature of most pituitary tumors and their retention of a response to negative feedback by hormones produced by target organs support this hypothesis.

Laboratory Studies
Laboratory tests include basal hormone levels and dynamic hormone measurements depending on the tumor studied. All tumors should have screening basal hormone measurements, which may include prolactin, thyrotropin, thyroxine, adrenocorticotropin, cortisol, LH, FSH, estradiol, testosterone, growth hormone, insulinlike growth factor-1 (IGF1), and alpha subunit glycoprotein. Dynamic hormone tests are performed to assess the functionality of a tumor and assist in differential diagnosis. They also can be used to assess anterior pituitary reserve. Thyrotropin-releasing hormone (TRH) causes elevation of serum prolactin and thyrotropin. Prolactinomas, hyperprolactinemic states, hyperthyroidism, and panhypopituitarism exhibit a blunted response. Gonadotropinomas respond paradoxically to TRH (LH, FSH, LH-beta, and alpha subunit should be measured). GHRH produces an elevation in growth hormone. This response is blunted in growth hormone deficiency, Cushing disease, and hypothyroidism. Other agents that may be used for this test include insulin, L-dopa, arginine, and clonidine. Acromegaly may produce a paradoxical reduction in growth hormone. Hyperglycemia suppresses serum growth hormone. This suppression does not occur in pituitary tumors secreting growth hormone, ectopic growth hormonereleasing tumors, Cushing syndrome, and anorexia nervosa. A paradoxical rise in growth hormone may be observed in acromegaly, acute illness, and chronic renal failure. Many people with acromegaly also show paradoxical growth hormone response to TRH and occasionally to GnRH.

CRH causes a rise in corticotropin. This response is exaggerated in Cushing disease but blunted in other causes of Cushing syndrome. When combined with inferior petrosal sinus sampling, this test may assist in differentiating Cushing disease from benign ectopic adrenocorticotropic hormone (ACTH) syndrome. Insulin-induced hypoglycemia causes a rise in corticotropin, cortisol, and growth hormone. A blunted response is observed in Cushing syndrome, growth hormone deficiency, hypothyroidism, and hyperthyroidism. Metyrapone causes a rise in morning serum 11-deoxycortisol and urinary 17hydrocorticosteroids (17-OH steroids). An exaggerated response occurs in Cushing disease, but no response is observed in other causes of Cushing syndrome. Dexamethasone suppression testing is used in Cushing syndrome evaluation. An overnight 1-mg dexamethasone dose fails to suppress morning serum cortisol in Cushing syndrome but is only a screening test. Low-dose and high-dose dexamethasone suppression tests assist, respectively, in establishing the diagnosis of Cushing syndrome and differentiating between Cushing disease and ectopic production of corticotropin. Cosyntropin testing and corticotropin infusion testing assist in assessing the hypothalamic-pituitary-adrenal axis for adrenocortical insufficiency. GnRH causes an increase in LH and FSH levels. This response is blunted in pituitary hypogonadism but exaggerated in primary hypogonadism. Test results, however, are not very dependable.

Imaging Studies
Pituitary imaging is important in confirming the diagnosis of pituitary macroadenoma and also for determining the differential diagnoses of other sellar lesions. Plain skull radiographs are poor at delineating soft tissues and so have been replaced by CT scanning and MRI. CT scanning is better at depicting bony structures and calcifications within soft tissues than either plain radiography or MRI. Differential diagnoses of tumors with calcification, such as germinomas, craniopharyngiomas, and meningiomas, are better determined with CT scanning. CT scans are valuable when MRI is contraindicated, such as in patients with pacemakers or metallic implants in the brain or eyes. Drawbacks include less optimal soft tissue imaging compared to MRI, use of intravenous contrast media that is needed to enhance images, and exposure to radiation. This makes MRI the modality of choice for pituitary imaging. MRI is more expensive than CT scans but is the preferred imaging study for the pituitary because it provides better visualization of soft tissues and vascular structures. No exposure to ionizing radiation occurs. Images are generated based upon the magnetic properties of the hydrogen atoms. With spin-echo, T1-weighted images, fat produces highsignal intensity images. Structures such as fatty marrow and orbital fat show up as bright images. T2-weighted images of structures with high water content, such as cerebrospinal fluid and cystic lesions, produce high-intensity signals, while structures with high fat content present with low-intensity signals. At least a 1.5-T magnet should be used for MRI of the pituitary.

Other Tests
Visual field testing should be performed, especially in tumors involving the optic chiasm. The severity of visual defects may dictate a more aggressive treatment course.

Histologic Findings
The histology of pituitary macroadenomas shows varying levels of neoplastic activity. Frozen sections are usually not dependable for definitive diagnosis. Hormonal immunohistochemical stains for neuroendocrine markers are useful, especially in the nonfunctioning tumors.

Medical Care
The goal of treatment is complete cure. When this is not attainable, reducing tumor mass, restoring hormone function, and restoring normal vision are attempted using medications, surgery, and radiation. Pituitary macroadenomas often require surgical intervention for cure. The exceptions to this rule are the macroprolactinomas, which usually have an

excellent response to medical therapy. The tumor size may be diminished but often does not disappear completely. Medical treatment can play a role in reducing tumor size, controlling hormonal excess, or correcting hormonal deficiency. Prolactin-secreting macroadenomas respond to dopaminergic agonists. The most frequently employed medications include bromocriptine, cabergoline, and, previously, pergolide. Quinagolide is an alternative with fewer adverse effects than bromocriptine. Prolactin-secreting macroadenomas are so responsive to medical therapy that surgery and radiation often are not used in treatment. Hyperprolactinemia from other lesions interfering with the hypothalamic-pituitary communication also responds to medical therapy. Pergolide was withdrawn from the US market March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. It is important not to stop pergolide abruptly. Health care professionals should assess patients need for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed, another DA should be substituted for pergolide. Growth hormone-secreting tumors should be treated surgically, often followed by radiation therapy. That acromegaly can be treated with surgery alone is very unlikely. However, debulking the tumor is very important. Radiation therapy results in 50% reduction in growth hormone levels within 2 years, followed by an additional 25% in the following 2 years. Thereafter, the growth hormone levels decline more slowly. Therefore, the lower the postoperative growth hormone level, the higher the chance of remission after radiation therapy. Medical treatment is used after surgery to suppress growth hormone secretion, awaiting the occurrence of the effects of radiotherapy. Octreotide is the treatment of choice. A long-acting formulation administered monthly is now available. Somatostatin must be administered as a continuous infusion, while shorter-acting octreotide is administered tidqid. Growth hormone receptor antagonists have been another addition to the treatment of acromegaly. Dopamine agonists also may be used but are not as effective as octreotide (approximately 30% of somatotropinomas respond). Corticotropin-secreting pituitary tumors are treated using surgery and radiation therapy (however, they are rather radioresistant). Medical therapy is reserved for patients whose therapy fails, those who decline other therapy, and those who cannot be treated otherwise. Medical therapy is divided into centrally acting agents that reduce corticotropin release and peripherally acting agents that reduce cortisol secretion or block cortisol action. Centrally acting medications (unfortunately effective in very rare occasions only) include bromocriptine, valproic acid, and cyproheptadine. Peripherally acting agents include ketoconazole, mitotane, and metyrapone. Use of such medications should be in combination with radiotherapy. Gonadotropin-secreting macroadenomas are treated surgically, followed by radiation. Medical therapy is reserved for those patients who decline definitive treatment. Bromocriptine or octreotide may be used. LH-releasing hormone antagonists may decrease hormone levels but do not affect the tumor size. Nonsecretory macroadenomas are treated surgically.[5] If surgery is contraindicated, octreotide or bromocriptine may be tried; however, the results are often disappointing. Thyrotropin-secreting tumors are treated surgically, followed by radiation therapy Octreotide is quite effective in such tumors and can be used as adjuvant therapy. Traditional radiotherapy using external beam radiation is used to complement surgery in inoperable cases or in patients declining surgery. The major drawbacks include delayed onset of action and high incidence of panhypopituitarism.[6]

Radiation therapy
Recent studies show the benefits of radiation.[7] Radiosurgery using a gamma knife employs a computer-assisted stereotactic mapping followed by several discrete radiation treatment fields to the tumor. This allows targeting maximal radiation to the tumor while minimizing radiation to the surrounding tissues. Incidence of hypopituitarism is less.

Advances with gamma radiation are associated with a very low incidence of postradiation hypopituitarism if the radiation dose is kept at less than 15 Gy.[8]

Surgical Care
Pituitary macroadenomas often require surgical extirpation for cure. Transsphenoidal surgery is the approach of choice.[9, 10, 11] Only about 1% of patients require a transcranial approach. Compared with remission rates of 90% in microadenomas, macroadenomas with significant extrasellar extension have remission rates of 15-37% when treated with surgery alone. Radiation therapy and medical treatment often complement surgery.[12] Intraoperative MRI findings correlate with prognosis of visual deficits after transsphenoidal decompression of the anterior optic pathways. The use of intraoperative MRI may prevent revision surgery for unexpected symptomatic remnants.[13] In a study of 13 patients, Elhateer et al reported on the effectiveness of fractionated stereotactic radiation therapy (FSRT) in the treatment of macroadenomas.[14] In 12 of the patients, FSRT was employed following tumor resection, while in 1 patient, it served as primary treatment. All but 4 of the patients had nonfunctional macroadenomas. After a median follow-up period of 24 months, the investigators found that local control in the patients was 100% and that 1 patient had a clinically complete response. According to the authors, the results indicated that FSRT is an effective means of tumor control in patients with pituitary macroadenoma and that it is associated with a low rate of radiation-related morbidity. (No patients were found to have radiation-induced optic neuropathy or radiation-related endocrine dysfunction.) The authors stated, however, that because the study contained so few patients with functioning tumors, they could not judge the hormonal response of macroadenomas to FSRT. Based on an observational follow-up study (median period, 5.25 y) of 30 patients with pituitary macroadenomas (10 patients with functioning adenomas and 20 with nonfunctioning lesions) that were refractory to conventional surgical and/or medical treatment, Schalin-Jntti et al also found FSRT to be a beneficial adjuvant therapy for these tumors.[15]

Consultations
When a pituitary macroadenoma is diagnosed, consultations with an endocrinologist, neurosurgeon, neuroradiologist, and neurophthalmologist should be considered.

Medication Summary
Medications are used to control excess hormone secretion or to replace deficient hormones.

Dopaminergic agents
Class Summary
These agents directly stimulate postsynaptic dopamine receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the secretion of hormones from the anterior pituitary by secreting an inhibitory factor, believed to be dopamine.

Bromocriptine (Parlodel)
Dopamine agonist used to normalize serum prolactin levels. Semisynthetic, ergot alkaloid derivative. Strong dopamine D2-receptor agonist. Partial dopamine D1-receptor agonist. FDA approved as an adjunct to levodopa/carbidopa but less effective than other dopamine agonists. Might relieve akinesia, rigidity, and tremor associated with Parkinson disease. Stimulates dopamine receptors in the corpus striatum. Approximately 28% absorbed from the GI tract and metabolized in the liver. Approximate elimination half-life is 50 h, with 85% excreted in feces and 3-6% eliminated in the urine. Initiate at low dosage and slowly increase dosage to individualize therapy. Assess dosage titration q2wk. Gradually reduce dose in 2.5-mg decrements if severe adverse reactions occur.

Cabergoline (Dostinex)
Dopamine agonist used to normalize serum prolactin levels. Long-acting dopamine receptor agonist with high affinity for D2 receptors. Prolactin secretion by anterior pituitary is under hypothalamic inhibitory control exerted through dopamine.

Pergolide (Permax)
Pergolide was withdrawn from the US market March 29, 2007. Potent dopamine receptor agonist at both D1 and D2 receptor sites. Approximately 10-1000 times more potent than bromocriptine on a mg-per-mg basis. Inhibits secretion of prolactin. Causes a transient rise in serum concentrations of growth hormone and decrease in serum concentrations of LH.

Growth hormone receptor antagonists

Class Summary
Used for the treatment of acromegaly.

Pegvisomant (Somavert)
Genetically engineered growth hormone receptor antagonist used to treat acromegaly. Useful in patients not responding to somatostatin analogues. May be used concurrently with somatostatin analogues after surgery and radiation.

Somatostatin analogues
Class Summary
Used to control symptoms resulting from excess hormone secretion.

Octreotide (Sandostatin)
Somatostatin analogue used to normalize growth hormone levels. Acts primarily on somatostatin receptor subtypes II and V. Inhibits growth hormone secretion and has multiple other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and GI peptides.

Further Inpatient Care

Correction of hormone imbalances should be attempted preoperatively. Adrenocortical insufficiency should be sought and corrected. Transient diabetes insipidus is common following surgery for macroadenomas. A triphasic response where diabetes insipidus is followed by hyponatremia and, later, diabetes insipidus again is more frequent following surgery for macroadenomas than microadenomas. Vasopressin may be required transiently. Permanent diabetes insipidus, however, is not frequent.

Further Outpatient Care

Monitor for remission by hormone assays and tumor size. Monitor for development of hypopituitarism. Radiation therapy may cause hypopituitarism months to years later.

Inpatient & Outpatient Medications

Medications are based on hormonal abnormalities. For instance, dopaminergic agents are used for hyperprolactinemia, and somatostatin analogues are used for acromegaly.

Complications
Complications result from mass effects and abnormal hormone function.[16] Pituitary apoplexy, which is an acute hemorrhagic infarction of a pituitary tumor, requires emergency decompression. It presents with adrenal crisis and a severe headache followed by coma and death within hours if not appropriately managed. Postoperatively, pituitary hormone insufficiency, including diabetes insipidus, hypothyroidism, and hypogonadism, may occur. Radiation treatment exceeding 60 Gy can be associated with optic nerve neuropathy and brain necrosis. Pituitary hormone insufficiency might present several years after treatment. Other complications include visual impairment, obesity, and memory impairment.

Prognosis
Prognosis is variable depending on patient status, comorbid conditions, tumor size, and functional status of the tumor. Small, nonfunctioning tumors that undergo curative surgical extirpation have an excellent prognosis compared to unresectable, giant macroadenomas. Tumors that continue to secrete excess hormone despite aggressive treatment carry a poor prognosis. Such cases include Cushing disease and acromegaly.[17] A meta-analysis showed that macroadenomas tend to enlarge more frequently (12.5 per 100 patient-years [95% CI 7.9 - 17.2] than microadenomas (3.3 per 100 patient-years [95% CI 2.1-4.5]).[18]