Chemotherapy: neurologic complications
May. 10, 2022
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Pituitary adenomas represent 9% of intracranial neoplasms. A new nomenclature, pituitary neuroendocrine tumors (PitNET), is proposed for these tumors in the 2021 WHO classification of central nervous system tumors (35). Typical presenting manifestations include amenorrhea, infertility, visual field abnormalities, and headache. Diagnosis is often made with brain MRI, visual field testing, and serum hormone assay. Prolactinoma, the most common type of pituitary adenoma, usually responds to therapy with a dopamine agonist such as bromocriptine or cabergoline. Transsphenoidal surgery, particularly the endoscopic approach, has evolved to become the preferred approach to refractory prolactinoma, other functioning adenomas, and macroadenomas. Stereotactic radiosurgery is emerging as a second-line option.
• Pituitary adenomas represent 9% of intracranial neoplasms.
• Typical presenting manifestations include amenorrhea, infertility, visual field abnormalities, and headache.
• Diagnosis is often made with brain MRI, visual field testing, and serum hormone assay.
• Prolactinoma, the most common type of pituitary adenoma, usually responds to therapy with a dopamine agonist such as bromocriptine or cabergoline.
• Rare refractory cases, large tumors, and pituitary adenomas that secrete other hormones are treated with transsphenoidal surgical resection first-line.
• Stereotactic radiosurgery has largely replaced external-beam radiotherapy as a second-line treatment option.
The pathologic classification of pituitary adenomas has changed considerably over time and has been influenced by advances in physiology, molecular biology, and genetics. The initial attempts at classification relied on hematoxylin and eosin staining of resected tissue. They were categorized as acidophilic, basophilic, or chromophobic. This scheme, however, failed to account for clinical manifestations or hormone secretion. Further attempt at a functional classification of these tumors utilized immunoperoxidase staining techniques to identify the hormones within adenoma cells. This form of analysis proves that acidophil and chromophobe cells may produce the same hormones (prolactin, growth hormone, or thyroid-stimulating hormone), whereas basophil cells produce any of the other anterior pituitary hormones (adrenocorticotropic hormone, beta-lipotropin, luteinizing hormone, or follicle-stimulating hormone). A more recent classification scheme, based on the cell lineage delineation, uses a combination of immunohistochemical biomarkers that includes pituitary transcription factors, hormones and low molecular weight keratins (03). This scheme not only identifies hormone producing tumors but subclassifies the nonfunctioning adenomas, with the identification of the hormone and transcription factor negative tumor named null cell adenoma, which has distinct characteristics from the most common gonadotroph adenomas (04). Of the hormone-secreting adenomas, 60% to 70% secrete prolactin, 10% to 15% secrete growth hormone, a small number secrete adrenocorticotropic hormone, and rare tumors secrete gonadotropins or thyroid-stimulating hormone (59).
The classification of neoplasms of the anterior adenohypophyseal cells by malignancy has not been clinically useful. Although pituitary adenocarcinoma characterized by metastases is extremely uncommon, these predominantly benign tumors have varying aggressive behavior with capacities for invading surrounding tissues (02). The attempt at a clear definition of this heterogenous group of tumors has led to the drop of the term atypical adenomas in the 2016 WHO revision of the classification of pituitary adenomas, such that proliferative and invasive markers will be used to define these high risk adenomas. There has also been a recommendation of the use of the term pituitary neuroendocrine tumors rather than adenomas (02).
Tumor size is frequently used to categorize pituitary tumors as microadenomas (less than 10 mm in diameter) and macroadenomas (10 mm or greater in diameter). Tumors greater than 30 mm along any plane are regarded as large adenomas, whereas tumors greater than 40 mm or with a volume of 10 cm2 or more are regarded as huge adenomas. The differing sizes portend different challenges. This radiologically based classification continue to be relevant particularly to the neurosurgeon in the era of evolving high-resolution neuroimaging.
Pituitary adenomas typically manifest as a result of mass effect on visual structures, endocrine abnormalities due to hormone hypersecretion, or a combination of both. Symptoms and signs of pituitary hypofunction are often observed as well. Incidental pituitary adenomas may be discovered on routine brain imaging, with varying rates reported for microadenomas (10% to 38%) and macroadenomas (0.16% to 3%) (41).
Mass effect from a pituitary adenoma is the most common cause of chiasmal dysfunction in adults, classically producing a bitemporal hemianopsia. Bitemporal scotomas, markedly asymmetric visual loss, foggy or dim vision, and superior bitemporal hemianopsia are often seen as well. These effects are explained by tumor expansion and compression of the optic chiasm that lies anterior and superior to the pituitary gland. Oculomotor paralysis sometimes occurs when a pituitary adenoma extends laterally to invade the cavernous sinus. The true cavernous sinus contents, including the intracavernous carotid artery, cranial nerve VI, and the sympathetic nerves en route to the eye, are in the reticular membrane, which forms the lateral wall (27). Any of these structures may be compromised by a pituitary lesion. Rarely, compression of the internal carotid artery may occur and produce cerebral ischemia. As with any space-occupying brain lesion, symptoms of elevated intracranial pressure may be elicited. Headache is reported to occur in 37.5% to 75% of patients with pituitary adenoma, predominantly presenting as migraine headache or tension-type headaches, although cluster headache and related headache symptomatology is known to occur (32; 28). Uncommonly, pituitary adenomas may invade the hypothalamus and produce autonomic dysregulation, hypothermia, diabetes insipidus, or somnolence. A number of other rare presentations have been described. These include third ventricle compression with obstructive hydrocephalus, CSF rhinorrhea, and seizures from temporal lobe indentation (31).
Clinical manifestations due to hormone excess are determined by the nature of the secreted hormone. Prolactinomas are the most common hormone secreting pituitary adenomas. The macroprolactinomas (less than 10 mm in diameter) are common in women, in which subtle changes in prolactin levels can alter menses; as a result, prolactinomas often present in female patients of childbearing age with amenorrhea, oligomenorrhea, or infertility. Galactorrhea commonly occurs and may be the only detectable abnormality on physical examination. Macroprolactinomas and the less common giant prolactinomas are more common in male patients, whereas subtle changes in prolactin levels are less evident. Thus, prolactin-secreting macroadenomas may exert hormone effects that go unnoticed for months or years. The tumor may not come to clinical attention until a male patient develops symptoms referable to the tumor mass or symptoms of hypogonadism such as impotence, gynecomastia, galactorrhea, and loss of libido, some of which may be recognized in retrospect (01; 13; 53). When a prolactinoma becomes large enough to compress normal pituitary tissue, thyroid and adrenal function are often impaired as well.
The endocrine manifestations of pituitary adenomas may result from an interruption of communication between the hypothalamus and the pituitary gland, or from direct hormone secretion by the tumor itself. In fact, mass effect from any lesion on the pituitary infundibulum may produce hyperprolactinemia. This phenomenon is termed the “stalk effect" and tends to cause mildly elevated prolactin levels (usually 100 to 200 ng/mL). Marked hyperprolactinemia (in excess of 200 ng/mL) is generally seen with true prolactin-secreting tumors. The stalk effect occurs because prolactin secretion is under inhibitory control by various hypothalamic factors, of which dopamine is the most important. As dopamine is released from the hypothalamus, it descends through the portal vessels to the adenohypophysis, where it inhibits the release of prolactin by prolactin-secreting cells (lactotrophs). Mass effect on the pituitary stalk can impair dopamine transfer to the adenohypophysis and thereby produce lactotroph hyperfunction (06).
The clinical manifestations of adenomas that secrete growth hormone are quite different from those seen with prolactinomas. Growth hormone hypersecretion in adults produces acromegaly, a syndrome characterized by acral growth and prognathism often in combination with visceromegaly, headache, and diabetes. Patients with acromegaly have a highly characteristic facial appearance. Diagnosis is often delayed because of the rarity of the disorder and the development of characteristic features over months to years. Growth hormone hypersecretion in prepubertal children causes gigantism.
Adenomas that produce adrenocorticotropic hormone may cause a syndrome of cortisol excess known as Cushing disease. Described by Harvey Cushing in 1932, Cushing disease is defined as a clinical state of hypercortisolism related to pituitary hypersecretion of adrenocorticotropic hormone. The majority (75%) of Cushing disease cases are the result of a pituitary adenoma (42). This is in contrast to cortisol excess related to exogenous steroids or primary hyperadrenalism, which is known as Cushing syndrome. Both the disease and the syndrome are clinically characterized by hirsutism, abdominal striae, hypertension, hypokalemia, acne, menstrual irregularity, centripetal obesity, immune suppression, muscle weakness and wasting, and psychosis. Pituitary adenomas that produce acromegaly or Cushing disease are generally microadenomas, so visual or other symptoms due to mass effect are unusual (59). Nelson syndrome, characterized by hyperpigmentation and high plasma adrenocorticotropic hormone levels despite adequate glucocorticoid replacement, results from the growth of residual pituitary tumor after bilateral adrenalectomy in patients with Cushing disease. These tumors often produce mass effect and tend to be aggressive and treatment-resistant (01).
Pituitary apoplexy is a relatively uncommon syndrome characterized by the sudden onset of severe headache, deterioration in visual acuity that may lead to visual loss, ophthalmoplegia, and decreased level of consciousness, often with abnormalities of the cerebrospinal fluid (hemorrhage or pleocytosis and elevated protein). There is also varying degree of hypopituitarism seen in patients at presentation. This life-threatening condition occurs following rapid expansion of an infarcted or hemorrhagic pituitary adenoma with subsequent mass effect on the suprasellar space and cavernous sinuses. The incidence of pituitary apoplexy has been quoted to occur in 2% to 7% of pituitary tumors when a combination of clinical, surgical, and histopathological findings are considered, although this percentage seems high when taking into account incidentally diagnosed pituitary adenomas. In a study of 185 patients with subclinical pituitary adenoma apoplexy, subclinical pituitary adenoma apoplexy was found to occur more frequently than acute pituitary apoplexy (64). Predisposing factors include Sheehan syndrome from postpartum hemorrhage, trauma, angiography, diabetic ketoacidosis, bromocriptine administration or withdrawal, radiotherapy, and cardiac surgery. Transsphenoidal surgery is often the preferred method of treatment for pituitary apoplexy with a debate on the timing of intervention. Patients have also been reported to do well with medical management. Though recovery is expected in patients who receive prompt treatment, panhypopituitarism is common after pituitary apoplexy. Published investigations suggest that vascular endothelial growth factor may play an important role in pituitary adenoma angiogenesis. Future work may help to explain why catastrophic infarction and hemorrhage sometimes occur (40).
Pituitary adenomas are typically benign neoplasms with risk to temporal vision and endocrine function. Phospho-histone H3 has been explored as a potential prognostic marker in non-functioning pituitary adenomas (24).
A 19-year-old woman presented with expressible galactorrhea for 3 months. She had never been pregnant. Her menarche was at 13 years of age, with an ensuing year of irregular menses. She had been amenorrheic since that time. She complained of occasional headaches but no other symptoms.
Humphrey visual field testing revealed asymmetric superior bitemporal field defects. The patient had not noticed any changes in her peripheral vision. The remainder of her neurologic and general examination was normal.
Endocrinologic screening revealed an elevated prolactin level of 400 ng/mL. MRI showed a heterogenous growth from the infundibulum of the pituitary gland measuring 3 cm by 2 cm with an avidly enhancing solid center. The right side of the lesion appeared cystic, with layering of proteinaceous fluid.
The patient was diagnosed with a pituitary adenoma (prolactinoma), and medical therapy with cabergoline was initiated. Galactorrhea subsided within 2 weeks, and a repeat formal visual field exam 3 months later showed an interval decrease in her bitemporal defects. Follow-up has continued for 16 months, at 6 month intervals, with stable visual fields. Serial imaging examination showed regression of the solid part of the enhancing tumor by 25%. Prolactin levels have decreased to slightly above normal values on continued oral therapy.
The precise genetic event that is responsible for pituitary tumorigenesis has not been identified. Until the 1990s, there was a debate among researchers about whether pituitary adenomas are the result of an intrinsic pituitary defect, or whether they develop in response to dysfunctional hypothalamic signaling. Thanks to studies using X-allele inactivation methods, it is now accepted that pituitary adenomas arise from neoplastic transformation of a single cell that is followed by monoclonal expansion (01). Thus far, no pharmacologic or environmental agent has been implicated in this process.
A number of studies have attempted to identify activating oncogene mutations or inactivating tumor suppressor gene mutations that might contribute to the pathogenesis of the tumor. An example of such an oncogene is present in about 40% of growth hormone-secreting pituitary adenomas. In these adenomas, there is a point mutation in the GNAS gene that codes for the alpha subunit of the Gs protein, producing a faulty G-protein subunit. This leads to excessive and unregulated growth hormone secretion (29; 33). Next generation sequencing has also led to the discovery of the point mutation in the ubiquitin-specific protease 8 (USP8) in about 40% to 62% of corticotroph adenomas (47; 33). Targeting this mutation and the downstream signaling pathway is being explored as potential pharmacological targets. Studies have identified a variety of tumor suppressor genes that may be involved in pituitary tumorigenesis. Unfortunately, it remains unclear at this time whether these mutations are causative or simply represent epiphenomena. For example, the PI3K/AKT/mTOR pathway has been associated with other brain and systemic neoplasms, and its role in pituitary adenomas is being explored (39). Additional evidence regarding tumor pathophysiology is derived from studies of patients with pituitary tumors due to familial syndromes. Germline mutations have been found in syndromic diseases such as multiple endocrine neoplasia type I (MEN1), McCune-Albright syndrome, isolated familial acromegaly, and the Carney complex (CNC). The gene responsible for MEN1 is found at chromosome locus 11q13. Some evidence suggests that loss of heterozygosity for a tumor suppressor gene at 11q13 may contribute to the progression of sporadic pituitary adenomas (38). Research has identified two novel mutations in MEN1 individuals with prolactinoma (44). One study identified non-MEN/non-CNC familial isolated pituitary adenomas (FIPA), and the FIPA patients tended to be younger at diagnosis than in sporadic cases. Prolactinomas from families with heterogeneous phenotypes were larger and more likely to have suprasellar extension (16). Germline mutation in CABLES1 has been associated with corticotroph adenoma (23). Another study combined chip-based technologies with genealogy data to identify germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) genes in individuals with pituitary adenoma predisposition (60). Further analysis suggests that aryl hydrocarbon receptor interacting protein genetic testing is a reasonable consideration in young patients with a positive family history (51).
Pituitary adenomas account for approximately 17% of intracranial tumors. The prevalence of occult pituitary adenomas at autopsy ranges from 3.1% to 22.5%, whereas symptomatic tumors in the general population are estimated at 0.020% to 0.025% (45; 55). Pituitary adenomas become increasingly prevalent with age. By the age of 80 years, more than 20% of pituitary glands have small adenomas (59). Only 3% to 7% of patients with pituitary adenomas are younger than 20 years old. Sex distribution shows an overall female to male ratio of about 2 to 1, higher in microprolactinomas (20 to 1) and adrenocorticotropic hormone-secreting adenomas (4 to 1). These figures may be subject to sampling error (20).
As no risk factors for spontaneous pituitary adenomas have been identified, no preventive regimen is available. Approximately 3% of surgically resected pituitary adenomas occur as part of a hereditary syndrome. Most hereditary tumors are associated with MEN1 syndrome. This autosomal dominant condition is characterized by the spontaneous development of tumors of the pituitary, pancreas islet cells, and parathyroid glands. Pituitary adenomas occur in 25% of patients with this syndrome and are most commonly growth hormone-secreting. Some tumors may secrete both prolactin and growth hormone (65). Genetic counseling is recommended for individuals with a family history of MEN1 who are contemplating pregnancy.
MRI is frequently adequate to distinguish pituitary adenomas from other sella turcica masses. There are some exceptions to this rule. Pituitary carcinoma, though rare, cannot be reliably diagnosed with neuroimaging. When this entity is suspected, biopsy should be considered, although even histologic features do not always permit accurate diagnosis. Tumors that arise from the neurohypophysis are also quite rare and cannot always be distinguished from anterior pituitary lesions. Other sellar masses that are occasionally confused with pituitary adenomas on neuroimaging include craniopharyngiomas, germ cell tumors, meningiomas, and hypothalamic gliomas. Because these neoplasms do not often involve the pituitary fossa and because they generally arise from suprasellar structures, MRI diagnosis is usually straightforward. Rathke cleft cysts, dermoid and epidermoid cysts, the empty sella syndrome, and carotid artery aneurysms have different signal intensity on MRI than pituitary adenomas. Pituitary metastasis may be diagnostically challenging from the standpoint of imaging. The presence of diabetes insipidus is a typical presenting symptom in pituitary metastasis that may help to distinguish this lesion from benign adenoma. One of the most challenging differential diagnoses is lymphocytic hypophysitis, an inflammatory syndrome seen primarily in young postpartum women. Enhancement of the pituitary stalk and inferior hypothalamus may be helpful in distinguishing this lesion from an adenoma. Other systemic inflammatory or granulomatous diseases may involve the pituitary and masquerade as adenomas. Examples include sarcoidosis, Wegener granulomatosis, Langerhans cell histiocytosis, and mycobacterial or spirochete infections. Rare lesions such as teratoma, pituitary lymphoma, and pituitary abscess are considerations as well (17).
Hyperprolactinemia has a variety of causes. Physiologic states such as pregnancy, nursing, nipple stimulation, and even stress may elevate prolactin levels. Antidopaminergic medications are often implicated as causes of hyperprolactinemia. Examples include many antipsychotics (both typical and atypical), selective serotonin reuptake inhibitors, metoclopramide, estrogens, and verapamil. As mentioned earlier, nonfunctional adenomas or other mass lesions that compress the pituitary stalk may cause hyperprolactinemia. Polycystic ovarian syndrome is a well-known cause (31). Other etiologies include primary hypothyroidism, chronic renal failure, cirrhosis, chest wall trauma, and seizures.
In individuals suspected of harboring a pituitary adenoma, a neurologic examination and hormone interrogation are required for accurate diagnosis. As progressive visual field deterioration is often the principle criterion on which surgical decisions are made, visual field testing is a critical portion of the neurologic exam in these patients. Referral to an ophthalmologist or neuro-ophthalmologist for formal visual field assessment is warranted. Levels of prolactin, growth hormone, morning cortisol, adrenocorticotropic hormone, luteinizing hormone, follicle-stimulating hormone, thyrotropin, and free T4 should be checked. Provocative and dynamic testing of hormone levels may be necessary to adequately define syndromes of hormone excess or deficiency. This evaluation is generally best supervised by an endocrinologist, but a brief summary of frequently used tests will be presented here:
Prolactin. Very high prolactin levels reliably indicate the presence of a lactotroph adenoma. Elevated levels that are less than 200 ng/mL may be the result of a microadenoma, medication effect, or any other sellar mass (49). Low prolactin levels in the presence of giant pituitary adenomas should raise suspicion of the "high-dose hook effect." This erroneous measurement results from saturation of both the capture and signal antibodies used in common laboratory assays. This problem can be avoided by diluting the sample and repeating the assay (05).
Growth hormone. Acromegaly is diagnosed in the appropriate clinical context when basal growth hormone levels are elevated on two occasions. Measurement of serum insulin-like growth factor is often helpful. For borderline cases, growth hormone measurement after suppression by an oral glucose load is crucial (31). Gigantism may occur when a growth-hormone secreting tumor presents in children.
Adrenocorticotropin. Elevated 24 hour urine free cortisol excretion associated with a high-normal or high ACTH concentration suggests the presence of an adrenocorticotropin-secreting adenoma. A dexamethasone-suppressed corticotropin releasing hormone test may be necessary to draw definitive conclusions (31).
Testing for hormone deficiency caused by a large pituitary mass is often necessary as well.
A synacthen test (ACTH stimulation test) may sometimes be necessary to diagnose hypoadrenalism in the presence of borderline values of cortisol. Replacement therapy for hypoadrenalism and hypothyroidism is important prior to surgical intervention to ensure cardiovascular safety. Hormonal replacement is usually lifelong.
Though plain skull films and head CT were once used frequently, MRI is now the imaging modality of choice in patients with suspected pituitary adenoma.
High resolution MRI with gadolinium optimally delineates tumor morphology. Even when circumstances are ideal, microadenomas may be difficult to detect. On routine postcontrast T1 MRI, microadenomas usually show fewer enhancements than normal pituitary tissue. Their presence may be suggested by deviation of the pituitary stalk or bulging of the gland. Macroadenomas may have the same signal characteristics as gray matter on T1 and T2 sequences. They usually show intense, often heterogeneous contrast enhancement that allows for straightforward diagnosis. Heterogeneous signal intensity on unenhanced MRI suggests necrosis, cyst formation, or hemorrhage. Hemorrhage detected by MRI is not uncommon, even in the absence of clinical signs of pituitary apoplexy. Benign invasive adenomas cannot be distinguished from rare pituitary carcinomas on imaging studies alone. Serial MRI can be used to monitor therapy and to delineate tumor hemorrhage, cyst formation, and necrosis (43). Dynamic MRI techniques may be necessary to distinguish residual tumor from postoperative changes (63).
Because pituitary tumors frequently produce visual impairment due to mass effect on the optic nerves or chiasm, neuro-ophthalmologic examination should be considered in any patient who reports visual changes or in whom imaging demonstrates tumor burden outside the sella turcica. This should be repeated within a few days after surgery if the patient is able to comply. Serial neuro-ophthalmologic and neuroimaging examinations may be performed at 6 months and 12 months postoperatively and yearly after that if stable.
Asymptomatic patients with incidentally discovered pituitary masses presumed to be adenomas are generally monitored with serial visual acuity testing, perimetry testing, and gadolinium-enhanced MRI. Anterior pituitary hormone levels should also be monitored, though most incidentally discovered adenomas do not secrete hormones. Neurosurgical intervention is recommended for patients who demonstrate tumor growth, visual loss, displacement of the optic chiasm by imaging, or hypopituitarism.
The management of patients with pituitary adenomas is multidisciplinary involving the neurosurgeons, neuroendocrinologists, neuropathologists, neuro-ophthalmologists, neuroradiologists, and radiation oncologists. Cases are discussed at pituitary tumor boards or neuro-oncology tumor boards, and the care of these patients has been advocated to take place in high volume centers to facilitate access to specialists and optimum care.
The goals of therapy for pituitary adenomas include decompressing the optic apparatus, reversing the endocrinologic manifestations of excess hormone secretion, reversing or replacing impaired pituitary function, preserving healthy pituitary tissue, and preventing damage to critical structures in close proximity to the pituitary gland. Because pituitary adenoma is a heterogenous disease, each patient must be treated with an individualized approach. Prolactinoma therapy will be considered first.
Asymptomatic microprolactinomas do not require therapy, as longitudinal experience proves that progression is uncommon. Patients whose only symptom is amenorrhea may opt for estrogen replacement therapy instead of dopamine agonists. Despite concerns that estrogen may promote adenoma growth, ample data demonstrate that exogenous estrogen has no effect on tumor progression (15). Prolactinomas are primarily treated medically, most often with ergot-derived dopamine agonists such as bromocriptine and cabergoline. Pergolide is a related agent approved for the treatment of Parkinson disease that is frequently used as well. Bromocriptine and pergolide are both D1 and D2 receptor agonists, whereas cabergoline acts at the D2 receptor alone. All of these agents inhibit the synthesis and secretion of prolactin. Multiple studies have shown that these agents are effective in shrinking pituitary adenomas and in lowering serum prolactin levels in the large majority of patients, but data have not yet identified the superior agent (15). An attractive feature of cabergoline is its 80 hour half-life that allows for once or twice weekly administration and improved patient compliance. This is in contrast to bromocriptine, which is administered two or three times daily. Side effects of cabergoline are reported to be less troublesome than those observed in bromocriptine-treated patients (61; 11). Also of note is that cabergoline is often effective in patients who have failed treatment with bromocriptine. The duration of dopamine agonist therapy in patients with prolactinoma is unclear, and many physicians treat indefinitely. Data indicate that cabergoline may be safely withdrawn in patients whose tumor becomes undetectable on MRI and whose serum prolactin level normalizes, though long-term follow-up of these patients has not yet been reported (14). Any of the dopamine agonists may cause nausea, orthostatic hypotension, and depression. These side effects tend to improve with time and can be prevented by slow dose titration. A rare but serious side effect of medical therapy occurs when tumor shrinkage reveals a dural or sellar defect. The result is CSF rhinorrhea, and surgical management is indicated.
In rare patients with prolactinoma who are refractory to medical therapy or cannot tolerate it, surgical resection may be performed. This is generally less effective than medication with substantial rates of persistent or recurrent hyperprolactinemia postoperatively. Radiotherapy may reduce tumor size and prevent further growth, but this modality tends to be ineffective in treating hyperprolactinemia (58).
With the exception of prolactinomas, resection of symptomatic pituitary adenomas is the first-line treatment. Surgery is nearly always necessary for treating tumors larger than 10 mm. The transsphenoidal approach either using the microscope and endoscope has evolved to be the preferred approach to 97% of pituitary tumors (12). The use of the endoscope has continued to gain traction in the resection of pituitary adenomas of various sizes with good visual and endocrine outcomes with low morbidity, especially because the nasoseptal flap was being utilized to reduce the risk of CSF leak and extended approaches. The efficacy of this approach has been proven across all age groups including well selected elderly patients without additional morbidities (46). Transcranial approaches do still have utility in selected cases with asymmetric extension to the frontal or temporal lobes and dumbbell shaped or fibrous tumors. Eighty-five percent of growth hormone-secreting microadenomas are curable with surgery alone, whereas only 40% of such macroadenomas may be cured with surgery alone. In some cases, octreotide, a somatostatin analogue, normalizes growth hormone levels and decreases tumor size. Potential side effects include diarrhea, nausea, and cholelithiasis (37). Pegvisomant, a novel growth hormone receptor antagonist, is now being used for refractory acromegaly; some results suggest that the agent is highly effective. In a study of 160 patients with acromegaly, 97% of those treated for at least 12 months showed an excellent response (57; 25).
Cushing disease is also primarily treated with transsphenoidal resection, with similar remission rates for microadenomas in both microscopic and endoscopic approaches, whereas the endoscopic approach was reported to have a higher remission and recurrence rates in macroadenomas (08). Endoscopic approach has also been reported to produce good results in invasive corticotroph adenomas. Radiotherapy may be used for persistent or recurrent disease. As cortisol levels may not normalize for up to 1 year after surgery, bilateral adrenalectomy is sometimes necessary. Medical treatment options include ketoconazole.
In one study of 26 patients with thyrotropin-secreting pituitary adenomas, all patients were reported to have excellent outcomes with the combination of surgical resection, somatostatin analogues, radiotherapy, and thyroid ablation (36).
External beam radiation therapy is not employed as a primary treatment modality in patients with pituitary adenomas (22; 07). It has been used in refractory situations. Higher doses are associated with an increased risk of complications. Anti-tumor effects may not be seen for months to years after administration (48).
Stereotactic radiosurgery allows for extremely precise dose distribution and is a reasonable second-line option when surgery is not feasible or has failed (26). Data with the longest follow-up period are available for Gamma knife (up to 80 months), however, studies have employed CyberKnife and linear-accelerator based stereotactic radiosurgery techniques. Both single-dose and hypofractionated techniques have been used (usually three to five fractions), with the latter offering reduced risk to the optic apparatus. Mean/median margin dose ranges between 14 and 20 Gy (26). Tumor control rates range from 83% to 100% over a follow-up interval, with significant rates of tumor shrinkage reported. Several series have reported minimal neurologic injury and low risk of hypopituitarism (19; 62). No neurocognitive dysfunction was found in patients receiving stereotactic radiosurgery with Gamma Knife (56). Nonsecretory pituitary adenomas appear to exhibit a better response and long-term prognosis than secretory adenomas with external beam radiation therapy and with stereotactic radiosurgery (18).
Chemotherapy is not generally considered a useful therapy for pituitary adenoma. However, a small number of patients have been treated with temozolomide, a chemotherapy agent that is approved for malignant gliomas. Low expression of a particular DNA repair enzyme known as O(6)-methylguanine-DNA methyltransferase (MGMT) has been shown to correlate with increased efficacy of temozolomide when used in malignant gliomas. MGMT is being explored in predicting the efficacy of temozolomide in treating pituitary adenomas and adenocarcinomas (10; 30; 34; 52; 54), although the data for this approach are very limited.
Experimental therapies for non-functioning pituitary adenomas include long-acting somatostatin (21).
Women with prolactinomas often present with infertility that generally resolves promptly with medical therapy. Pregnancy is associated with lactotroph hyperplasia, and reports of pituitary adenoma growth during pregnancy abound in the literature. This problem first appeared in the 1970s when bromocriptine therapy became commonplace. Large studies of patients with microprolactinoma demonstrate that the actual likelihood of tumor enlargement during pregnancy is quite small. Even when a microprolactinoma does enlarge, symptoms referable to the tumor are rare. Symptomatic enlargement usually responds to medical therapy. Macroprolactinomas are more likely to grow during pregnancy. In patients with these tumors, suspicion of tumor growth should prompt MRI and formal visual field testing. Ample data support the safety of bromocriptine therapy during pregnancy, so this is the first-line agent for pregnant women who require medical treatment. Surgery is an alternative for bromocriptine non-responders. A number of reports suggest that cabergoline therapy is safe in pregnancy as well. However, because long-term experience with cabergoline is limited, most providers favor bromocriptine (09).
Most patients with pituitary adenoma are not at increased risk when they receive anesthesia for surgical procedures. There are rare exceptions. Patients with thyrotoxicosis due to thyrotropin-secreting adenomas are at increased risk for tachyarrhythmia and should be treated prior to the induction of anesthesia. Patients with Cushing syndrome from adrenocorticotropic hormone-secreting adenomas are at risk for severe hypertension and hyperglycemia during surgery. Patients with acromegaly have an increased risk of airway-related complications compared to unaffected patients (50). Patients with nonfunctional adenomas may also be subject to increased anesthesia risk because of pituitary insufficiency. Thyroid and glucocorticoid replacement often must be initiated prior to surgery in these patients in order to prevent adverse outcomes.
Rimas V Lukas MD
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novocure for speaking engagements, honorariums from Novocure and Merck for advisory board membership, and research support from BMS as principal investigator.See Profile
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