Pituitary Tumors

Published on 09/04/2015 by admin

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24 Pituitary Tumors

Iris C. Gibbs, MD, Francesco Tuniz, MD, Edward R. Laws, MD, FACS, Laurence Katznelson, MD

Pituitary tumors are common, representing 10% to 20% of all intracranial tumors. These tumors are broadly classified according to whether they secrete excessive amounts of pituitary hormones or not. The secretory tumors typically exert morbidity by causing metabolic, somatic, and hormonal dysregulation, in addition to local mass effects from tumor growth. The nonfunctioning tumors may impair neurologic function by local tumor extension beyond the confines of the sella turcica into the adjacent cavernous sinuses, optic chiasm, and optic nerves, and compromise hormonal function by compression of the normal pituitary gland. The goals of treatment, therefore, are to minimize the effects on endocrine and neurologic function.

As imaging, surgical, medical, and radiation techniques have dramatically evolved over the past decade, the management of pituitary tumors increasingly requires a multidisciplinary team including neuroradiologists, neurosurgeons, radiation oncologists, and neuroendocrinologists. Although transsphenoidal microsurgery and medical therapy are considered first-line treatments of these tumors, radiotherapy remains a well established option for residual, recurrent, refractory, or unresectable tumors. In the last several years, conventional radiotherapy has given way to more modern radiation techniques, such as stereotactic radiosurgery, image-guided radiotherapy, and fractionated stereotactic radiotherapy, that allow unprecedented dose conformality and accuracy of dose delivery.

Epidemiology

Pituitary adenomas are benign neoplasms and comprise the majority of tumors arising in the sella turcica. With approximately 1 in 10,000 people diagnosed annually, these neoplasms are common in the general population.¹ According to updated Central Brain Tumor Registry of the United States (CBTRUS) data, pituitary adenomas account for approximately 9% to 11% of all primary intracranial tumor diagnoses.²^,³ However, the epidemiology of pituitary adenomas is complicated by the high frequency of small, asymptomatic tumors. Thus, tumor registry data likely underestimate the true prevalence of pituitary tumors. Better estimates of the true prevalence of pituitary adenomas are derived from studies of autopsy specimens or incidental findings on imaging scans. In a recent meta-analysis, the prevalence of pituitary adenomas was determined to be 16.7%, (14.4% from autopsy studies and 22.5% from radiography studies).⁴ In addition, a recent cross-sectional case-finding survey conducted in a province of Belgium concluded that the prevalence of pituitary adenomas might be even 3 to 5 times higher than previous estimates.⁵

Although the incidence varies according to age, gender, and ethnic group, women are reported to present more frequently than men; this perhaps may reflect the relative contribution of prolactinomas and corticotrophin secreting tumors. Seventy percent of these tumors present between the ages of 30 and 50 years old. However, 3% to 7% occur under the age of 20 years, with a low incidence in childhood that increases during adolescence.

Anatomy

Embryologically, the pituitary gland originates from two discrete parts of the developing embryo: (1) Rathke’s pouch, a dorsal evagination of ectodermal tissue immediately anterior to the buccopharyngeal membrane, and (2) the infundibulum, a ventral extension of the diencephalon just caudal to the optic chiasm. The former differentiates ultimately to form the anterior lobe of the pituitary gland (adenohypophysis). The infundibular process gives rise to the posterior lobe of the pituitary gland, also known as the pars nervosa or neurohypophysis.

The average weight of the pituitary gland at birth is about 100 mg. Rapid growth occurs in childhood, followed by slower growth until the adult weight (approximately 500 to 600 mg) is attained in the latter part of the second decade. The adult gland measures approximately 10 mm in length, 10 to 15 mm in width, and about 5 mm in height.

The anterior pituitary gland, which constitutes the bulk of the gland’s size and weight, produces six established hormones: thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH), and prolactin (PRL). These hormones serve both trophic and hormone stimulatory functions.

The anterior pituitary is the most richly vascularized mammalian tissue, receiving about 0.8 ml/g/min of blood from the portal system. After transmitting hypothalamic regulatory factors to the adenohypophysis via the hypophyseal stalk and receiving hormones secreted by the anterior lobe, the capillaries reconstitute themselves into efferent lateral hypophyseal veins, which drain into the cavernous sinus.

The posterior lobe secretes oxytocin and vasopressin. The latter is also sometimes called antidiuretic hormone (ADH), because one of its principal physiologic effects is retention of water by the kidney. These peptides are produced in the hypothalamus and then pass to the neurohypophysis via the 100,000 nerve fibers comprising the hypothalamo-hypophyseal tract. From the posterior lobe, the hormones are released into the general circulation in response to electrical activity at the axon endings.

The pituitary gland is situated within the hypophyseal fossa, a fibro-osseous compartment near the center of the cranial base. This fossa is demarcated laterally and superiorly by reflections of dura and elsewhere by the sella turcica (Fig. 24-1), a depression in the body of the sphenoid bone. The diaphragma sellae is an extension of the dura that separates the pituitary from the neural structures located superiorly including the optic chiasm. A central perforation of the diaphragma sellae allows for passage of the infundibulum. The folds of dura mater that form the lateral walls of the hypophyseal fossa contain the cavernous sinuses, which consist of a series of compartmentalized venous channels separated by fibrous trabeculae. The oculomotor nerve, trochlear nerve, and first two divisions of the trigeminal nerve are embedded in the lateral wall of the cavernous sinus, lying between the endothelial lining and the dura mater, whereas the abducens nerve is contained within the sinus itself. The cavernous sinus also envelops a portion of the internal carotid artery and the sympathetic nerve plexus encircling it.

FIGURE 24-1 • Radiograph of sella turcica.

Clinical Presentation

Secretory pituitary tumors present with clinical signs and symptoms attributed to disorders associated with the relevant hypersecreted hormone (Table 24-1). The most common hypersecretory tumor type is prolactinoma. Prolactinomas cause amenorrhea and galactorrhea in women and impotence and infertility in men. The second most common functioning-pituitary tumor is a GH-secreting adenoma which results in acromegaly in adults and in gigantism in children. Cushing’s disease results from the excessive secretion of cortisol as a result of an ACTH-secreting tumor. In the setting of an ACTH-secreting tumor, surgical bilateral adrenalectomy may lead to Nelson’s syndrome, a disorder characterized by aggressive growth of the primary corticotroph adenoma. TSH-secreting adenomas, characterized by thyrotropin-induced hyperthyroidism, are rare. Nonfunctioning pituitary adenomas, arising in the majority of cases from the gonadotropin-producing cells, are not associated with a classical hypersecretory syndrome.

Table 24-1 Clinical Syndromes Associated With Hormonally Functional Pituitary Adenomas

Hormone Produced	Clinical Syndrome
Prolactin (prl)	Amenorrhea, galactorrhea in women Impotence, infertility in men

Growth hormone (GH) Acromegaly, gigantism Adrenocorticotropic hormone (ACTH)

Cushing’s disease

Nelson’s syndrome (after adrenalectomy)

Thyroid-stimulating hormone (TSH) Hyperthyroidism

Tumors arising in the pituitary may cause compression of the native pituitary gland and resulting hyposecretion of pituitary hormones, leading to hypopituitarism. Additionally, owing to the proximity of the pituitary gland to several important cranial nerves such as the second, third, fourth, and sixth cranial nerves and vascular structures like the carotid arteries at the skull base, tumor extension may present with cranial nerve abnormalities. Extension laterally into the cavernous sinuses may therefore cause diplopia, opthalmoplegia, ptosis, diminished corneal sensation, or facial paresthesias in the upper face. If extension occurs superiorly the optic chiasm and hypothalamus are typically affected, whereas inferior growth causes extension into the sphenoid sinus. Large tumors that are allowed to grow unabated can ultimately extend into the temporal lobe, third ventricle, and posterior fossa.

Although pituitary tumors are classified according to whether they are associated with excessive production of hormones, they are also categorized as either microadenomas (tumor diameter less than or equal to 10 mm) or macroadenomas (tumor diameter greater than 10 mm). Corticotroph and lactotroph adenomas tend to be microadenomas, whereas the other functional and the nonfunctioning adenomas are usually macroadenomas at diagnosis.

Rarely, patients may present with pituitary apoplexy, acute infarction and hemorrhage of a pituitary adenoma. Apoplexy usually occurs in macroadenomas and is accompanied by severe headache, altered consciousness, opthalmoplegia, and visual deficits including blindness. Imaging studies usually reveal intratumoral hemorrhage (sometimes ischemic changes). These patients present with severe hypopituitarism and require urgent medical care for administration of stress doses of steroids, fluid administration, and pain control. Urgent surgery is also generally warranted to avoid potential permanent sequelae.

The evaluation of patients with pituitary tumors includes (1) thorough history and physical examination with detailed neurological examination, (2) comprehensive endocrine evaluation, (3) magnetic resonance imaging (MRI) with contrast and thin sections, and (4) neuro-opthalmologic examination with visual field tests. Other tests may be warranted including skeletal survey in the setting of acromegaly.

The modified Hardy classification is sometimes used to describe the tumor size, local growth pattern and extension.⁶^,⁷ Table 24-2 summarizes the grading of sellar floor destruction and staging of suprasellar or parasellar extension of pituitary adenomas on the basis of radiographic and operative findings.

Table 24-2 Grading of Pituitary Adenomas

Grading of Sellar Floor Destruction
Intact sellar floor	I	Sella normal or focally expanded, tumor <10 mm
Intact sellar floor	II	Sella enlarged, tumor ≥10 mm
Sellar floor not intact	III	Localized perforation of the sellar floor
Sellar floor not intact	IV	Diffuse destruction of the sellar floor
	V	Spread via cerebrospinal fluid or blood
Staging of Degree of Suprasellar/Parasellar Extension
	0	Confined within sella
Suprasellar extension	A	Occupies suprasellar cistern
	B	Obliteration of the recesses of the third ventricle
	C	Gross displacement of the third ventricle
Parasellar extension	D	Intradural extension into anterior, middle, or posterior cranial fossa
Parasellar extension	E	Extension into or beneath cavernous sinus

Types of Pituitary Adenomas

Secretory Adenomas

Prolactinoma

Prolactinomas are the most common type of pituitary adenoma, and account for approximately 40% to 45% of all pituitary tumors.⁸ In young adults, prolactinomas are more common in women, though this gender discrepancy is less apparent in middle-aged subjects. This gender discrepancy may reflect earlier detection in women, as hyperprolactinemia may cause oligo/amenorrhea, galactorrhea, infertility, and androgenization with hirsutism and acne. By contrast, diagnosis is often delayed in men, as the primary symptoms include reduced sexual function and libido.⁹ The finding of a higher prevalence of macroprolactinomas (>1 cm) and accompanying local mass effects in men may reflect this delay in diagnosis, though a gender effect on prolactinoma growth may be present as prolactinomas in men have higher proliferative indices (e.g., Ki-67) than in women.¹⁰^,¹¹ In all subjects, indications for therapy include the presence of hypogonadism, bothersome galactorrhea, infertility, headache, and local mass effects including visual field loss. The primary mode of therapy is medical with use of dopamine agonists, which rapidly reduce prolactin secretion and pituitary adenomas size in more than 90% of subjects. Administration of the dopamine agonist bromocriptine, either daily or in split daily doses, results in normalization of serum prolactin or return of ovulatory function in 80% to 90% of subjects.¹² Another dopamine agonist, cabergoline, is an ergot-derived dopamine agonist that is administered orally once or twice a week and, in macroprolactinomas, can normalize serum prolactin in 75% and reduce tumor size by about 33% in two thirds of cases.¹³ Cabergoline may be more efficacious and better tolerated than bromocriptine.¹⁴ A potential concern with cabergoline is the finding that use of high doses of cabergoline for Parkinson’s disease may be associated with an increased risk of valvular heart disease,¹⁵^,¹⁶ although the relevance of this finding to prolactinoma management is unclear. Surgery and radiation therapy are indicated in situations where medical therapy fails or the medication is poorly tolerated, or there is a significant cystic component (which does not respond fully to dopamine agonist therapy).¹⁷ Because administration of a dopamine agonist at the time of radiosurgery may limit long-term efficacy, it has been suggested that dopamine agonists should be withheld at the time of radiation treatment.¹⁸

Acromegaly

Acromegaly is a chronic, debilitating disease characterized by hypersecretion of GH and elevated levels of insulin-like growth factor-1 (IGF-1). This is an uncommon disorder, with prevalence for example in the Newcastle area of Great Britain of approximately 53 individuals per million and an incidence of 3 to 4 new cases per million over 11 years,¹⁹ although a recent study from Belgium suggests that the prevalence may be at least five times higher.⁵ More than 95% of cases are due to a pituitary, somatotroph adenoma, but, in rare cases, acromegaly may be due to neoplasms ectopically producing either GH or GH-releasing hormone.²⁰ Because of the slowly progressive, insidious nature of acromegaly, the diagnosis may be delayed for up to 10 years.²¹^,²² This delay in diagnosis may exaggerate the complications due to the tumor and GH hypersecretion, and is consistent with the finding that the majority of tumors are macroadenomas at detection. Diagnosis and disease control are imperative, as acromegaly is associated with enhanced, premature mortality, and this risk may be negated with biochemical control, including normalization of serum IGF-1 and attainment of safe GH levels.²³^,²⁴ Acromegaly is also associated with comorbidities including hypertrophic cardiomyopathy, sleep apnea syndrome, arthropathy, colon polyps, carpal tunnel syndrome, along with headaches: biochemical control can significantly improve most of these outcomes as well. Transsphenoidal surgery is the treatment of choice for most patients because it leads to a rapid fall in serum GH levels, is necessary for tumor debulking if there are local mass effects, and, in contrast to medical therapy, may lead to biochemical cure (vs long-term medical “control”).

Approximately 70% to 80% of patients with microadenomas and <50% of patients with macroadenomas attain biochemical normalization after surgery.²⁵^,²⁶ Medical therapy is largely utilized as adjuvant therapy for patients who have failed surgery. Somatostatin analogs (octreotide and lanreotide) are available in monthly depot preparations, and control GH and normalize serum IGF-1 levels in approximately 50% to 70% of cases.²⁷ Dopamine agonists, including cabergoline and bromocriptine (both oral agents), are in general less effective than somatostatin analogs.²⁸ The GH receptor antagonist, pegvisomant, is highly effective in reducing serum IGF-1 levels, and is often utilized as a secondary agent for subjects with incomplete or lack of response to somatostatin analogs.²⁹ Radiation therapy is considered as an adjuvant option for patients who have failed surgery and/or are unresponsive to or poorly tolerant of medical therapy. One study has suggested that concomitant administration of a somatostatin analog at the time of radiotherapy may be radioprotective,³⁰ though this finding was not reproduced in another study involving radiosurgery for acromegaly.³¹ Nevertheless, it is common practice to withhold somatostatin analogs at the time or radiation treatment, if possible.

Cushing’s Disease

Cushing’s disease results from overproduction of glucocorticoids because of excessive ACTH secretion by a corticotroph cell tumor of the pituitary gland. Cushing’s disease is uncommon, with an incidence between 0.7 and 2.4 cases per million per year.³² Consequences of Cushing’s disease include obesity, diabetes mellitus, hypertension, muscle wasting, osteoporosis, depression, coagulopathy, and cognitive deficits, and the 5-year cardiovascular mortality for untreated disease is 50%.³² The primary therapy is endonasal, transsphenoidal resection, and remission rates in patients with a microadenoma undergoing selective adenomectomy by an expert pituitary surgeon are in the range of 65% to 90%.³³^,³⁴ The recurrence rate in these patients may approach 20% at 10 years,³³^,³⁵ and may reflect dura mater invasion. In patients with persistent disease despite surgery, options include radiation therapy, medical adrenalectomy, and surgical adrenalectomy. Radiation therapy is reserved in an adjuvant role, in subjects with persistent, recurrent Cushing’s disease. Because of the lack of available medical therapeutics that target the pituitary adenoma, medical therapy, including use of ketoconazole, metyrapone, aminoglutethamide, and mitotane, is directed at reducing adrenal gland production of cortisol, and is largely utilized as a temporizing agent while awaiting effects of radiotherapy or plans for further surgery. Bilateral surgical adrenalectomy is a definitive treatment that provides immediate control of hypercortisolism, though the resultant adrenal insufficiency will require lifelong glucocorticoid and mineralocorticoid replacement therapy. A potential complication of bilateral adrenalectomy is Nelson’s syndrome, characterized by elevated serum ACTH levels, hyperpigmentation, and progressively enlarging, often invasive, pituitary corticotroph tumors.³⁶^,³⁷ The ACTH-producing adenomas in Nelson’s syndrome are aggressive, and surgical resection may be difficult. Directed radiotherapy would be indicated in this situation.

Nonfunctioning Pituitary Adenomas

Because patients with nonfunctioning pituitary tumors show no evidence of hypersecretory syndromes such as Cushing’s disease or acromegaly, these tumors are often detected incidentally, or in the workup of visual field loss, headache, modest hyperprolactinemia (from compression of the hypophyseal stalk), or hypopituitarism. Though these adenomas are called nonfunctioning because of the lack of an associated hypersecretory syndrome, these tumors are comprised of different subtypes. The detection of gonadotropin hormone and steroidogenic factor-1 production in a subset of tumors allows the classification of such tumors as gonadotrophic in origin.³⁸^,³⁹ Null cell and oncocytomas are terms relating to tumors that lack glycoprotein hormone production, though these terms are largely historical. Clinically nonfunctioning adenomas with invasive growth, elevated mitotic index, Ki-67 labeling index >3% and extensive nuclear reactivity for p53 are considered atypical, although the impact of this diagnosis on management strategies is unclear.³⁸ The primary mode of therapy of nonfunctioning adenomas is surgery. However, because these tumors are often detected incidentally and there is a delay in diagnosis, these adenomas are often macroadenomas with extrasellar extension at diagnosis, and surgery is utilized for decompression of adjacent structures and is usually subtotal in extent.⁴⁰ Medical therapies, including somatostatin analogs, are of limited use for these tumors.⁴¹ Radiation therapy is utilized in an adjuvant role for residual tumors following surgery, particularly in adenomas that involve the cavernous sinus.

Surgery

The goals of surgery for pituitary tumors are to (1) remove as much abnormal hormonally active tissue as possible; (2) eliminate tumor mass effect on the optic pathways; (3) preserve normal pituitary function; and (4) minimize the potential for recurrence. The most common surgical approach to these tumors is a transsphenoidal procedure to debulk the lesion and decompress parasellar and suprasellar structures (Fig. 24-2). Historical approaches to transsphenoidal surgery including sublabial and transnasal, transseptal surgery, although still useful, have been progressively supplanted by the techniques of direct transnasal transsphenoidal microsurgery using either a microscope or endoscope.⁴² Transsphenoidal surgery yields low morbidity and mortality rates and leads to improvement in visual symptoms in 87% to 90% of cases. For suprasellar tumors that are difficult to resect transsphenoidally, a variety of transcranial approaches (pterional, subfrontal, anterior interhemispheric, and transcallosal) allow adequate visualization and decompression of the optic nerves and chiasm. Surgical decompression remains the treatment of choice for symptomatic pituitary tumors. A common indication for surgery of pituitary adenomas is a macroadenoma that produces progressive visual loss from mass effect. In some cases, hemorrhage or necrosis into an existing pituitary tumor can cause precipitous visual loss associated with headache, cranial neuropathies, and sometimes acute adrenal insufficiency, a condition termed pituitary apoplexy. For prolactinomas, a pharmacologic approach is ordinarily attempted before surgery. Prolactinomas shrink dramatically with medical management (dopamine agonist therapy, usually bromocriptine or cabergoline); however, in rare cases some tumors (particularly cystic lesions) may be refractory to medical treatment, do not shrink, and maintain persistently high levels of prolactin. Alternatively, some patients may not tolerate effective doses of medical therapy. These tumors may require surgical removal.

FIGURE 24-2 • Nonsecreting pituitary adenoma. A, Preoperative coronal postcontrast MRI showing a sellar pituitary adenoma with suprasellar extension obscuring the visual pathways. B, Postoperative coronal MRI image showing resolution of the visual pathways.

Transsphenoidal extirpation of a microadenoma in Cushing’s disease is also superior to conventional radiation therapy and medical management in obtaining prompt and long-term remission. There is no effective medical management of Cushing’s disease at present; agents used are merely suppressive of adrenal glucocorticoid production and cannot safely be used for long-term treatment. Often, failure of previous medical or radiation therapy may warrant surgical intervention to treat residual tumor.

For all pituitary adenoma subtypes, postoperative anterior pituitary insufficiency has been reported to range from 1% to 27%.⁴³ Immediate postoperative polyuria and delayed hyponatremia must be considered in the early postsurgical follow up. Following transsphenoidal surgery, transient central diabetes insipidus (DI) has been reported in 10% to 60% of cases. However, permanent DI is uncommon, and has been reported in 0.5% to 15% of surgically treated patients. Studies using endoscopic approaches report generally report lower rates of this complication. In a recent quality of life study after endoscopic pituitary surgery, transient DI occurred in 5.5% and there were no cases of permanent DI.⁴³ In this study, worsening of preoperative visual function was present in 1% to 4% of patients and postoperative CSF leak and meningitis occurred in 0.5% to 3.9% of cases. The development of the endoscopic transsphenoidal approach to the pituitary region, which has similar indications to conventional transsphenoidal microsurgery, offers potential advantages over traditional surgical approaches because of its minimal invasiveness and panoramic visualization.

According to published series, long-term tumor control after transsphenoidal surgery alone ranges between 50% and 80%.⁴⁴ Recurrences can develop over time and as many as 16% of patients who have pituitary adenoma may experience recurrent tumor growth within 10 years after surgical intervention. The incidence of recurrence has been correlated with dural invasion.⁴⁵ Only 6% of patients experiencing recurrence requiring repeat surgery. Recurrent or residual tumors may require additional medical or radiation therapy.

Radiotherapy

Principles, Indications, and Clinical Results of Radiation Therapy for Pituitary Adenoma

Radiation is generally applied in the setting of residual or recurrent tumor following surgery with the goals of preventing tumor growth and normalizing elevated hormone levels. Studies evaluating radiation therapy report excellent tumor growth control rates of more than 95% at 10 years and more than 90% at 20 years (Table 24-3).⁴⁶^–⁴⁸ Because these are considered benign tumors and patients generally have long life expectancies, care must be taken to minimize the exposure of radiation to normal tissues and to avoid radiation complications.

Table 24-3 Selected Series of Conventional Radiotherapy for Pituitary Adenoma

Studies have shown that there is a dose response for tumor control. For example, Grigsby ⁴⁹ et al. determined that tumor control was only 28.6% when tumors were treated with <30 Gray (Gy). Ninety-four percent tumor control was achieved with 50 to 54 Gy; 85% with 40 to 49.99 Gy; and 75% with 30 to 39.99 Gy. Investigators at University of Florida determined that late recurrences can be largely avoided and that durable tumor control, more than 90% is achievable with radiation doses of ≥45 Gy in 25 fractions.⁵⁰ No significant dose response has been established for conventionally fractionated radiation doses between 45 Gy and 60 Gy. Therefore, the current accepted treatment dose schedule is 45 Gy in 1.8 Gy fractions for most pituitary adenomas, with 50.4 Gy in 1.8 Gy fractions being reserved for TSH and ACTH producing tumors.

For hormonally-active tumors, tumor control is also defined by control of hypersecretion. The normalization of hormone levels appears to increase over the length of follow-up. In Cushing’s disease, radiotherapy yields remission rates of approximately 50% to 95%, with most patients achieving normalization of plasma and urine cortisol within 2 years of treatment.⁵¹^–⁵³ The interpretation of results is more complicated for GH tumors because there is variability in the definitions of endocrine remission. For acromegaly, the time to 50% reduction of GH levels after radiotherapy has been reported to be approximately 2 years, and 75% by 5 years.⁵⁴ Using GH <5 mU/L and normal IGF-1 levels as more strict criteria for endocrine cure, Biermasz et al. showed that both criteria were met in 68% of patients over the mean follow-up of 123 months.⁵⁵ Normalization of prolactin levels in prolactinoma occurs in approximately 45% to 90% of cases at 5 to 10 years.^49,^56,⁵⁷

Radiotherapy Techniques and Treatment Planning

In preparation for radiotherapy, patients are typically immobilized with a rigid tilted head holder. The head and neck flexed and the chin tucked such that the head is held at roughly a 45-degree angle. This position is held in place by a thermoplastic facemask. Conventional radiotherapy treatment techniques for pituitary tumors include (1) the bicoronal wedged arc technique where bilateral 110-degree arc rotations are used with a 30-degree wedge (the wedge is reversed for the contralateral arc), and (2) the 3-field technique that uses a 3-field fixed beam arrangement of one anterior oblique and two lateral fields. Three-dimensional treatment planning that uses 4 to 6 coplanar and noncoplanar fields reduces the volume of brain tissue in the high dose region. At many institutions, conventional radiotherapy techniques using simple immobilization and limited beam angles have been largely supplanted by modern techniques including IMRT, fractionated stereotactic radiotherapy, and stereotactic radiosurgery. Improvements in immobilization with more precise thermoplastic masks, fixed or relocatable frames allow reduction of the planning margin from 1.5 to 2 cm down to 0.5 to 1.0 cm. Figure 24-3 shows an example of a 7-field coplanar and noncoplanar IMRT radiation isodose plan.

FIGURE 24-3 • IMRT isodose colorwash for residual nonsecreting pituitary adenoma: Axial (A) and sagittal (B) radiation dose colorwash images showing a 7-field IMRT (fields numbered at the entry angle) radiation plan for pituitary adenoma (red line). Prescription dose of 4500 cGy (pink range of the spectrum). Notice the dose heterogeneity indicated by doses exceeding 5000 cGy within the target tumor.

Complications of Radiotherapy

Potential late complications of radiotherapy include hypopituitarism, visual loss, secondary tumors, radiation brain necrosis, and possibly cerebral strokes.

Hypopituitarism is common after pituitary irradiation. This risk appears to increase over time. It is estimated that at least one half of patients receiving pituitary radiotherapy at suggested doses will develop deficiency in at least one anterior pituitary hormone within 5 years of radiotherapy. Deficiencies of growth hormone are typically the earliest deficit to be detected followed by deficiencies of gonadotropins, and finally deficits in thyrotropin and adrenocorticotropin. Radiotherapy does not generally result in damage to posterior pituitary ADH, thus, is not implicated in DI.

The risk of visual loss after pituitary radiotherapy is estimated to be less than 1% using modern techniques and conventional fraction sizes. Higher risks of visual loss, over 2%, have been correlated with higher fraction sizes. Although the development of secondary radiation-induced tumors is relatively infrequent, a study of 334 patients treated by postoperative radiotherapy with more than 3760 person-years of follow-up determined that the relative risk of developing a secondary tumor in these patients was 9.38 compared to the normal population.⁵⁸ In this study, the cumulative risk of a second brain tumor at 10 years was 1.3% and 1.9% at 20 years. Brain necrosis is exceedingly rare at doses of 45 to 50 Gy in <2 Gy. Becker et al. reported a long-term overall risk for brain necrosis 0.2% in 1,388 patients receiving pituitary irradiation.⁵⁹

Stereotactic Radiosurgery for Pituitary Adenoma

A variety of stereotactic radiosurgery techniques using gamma (γ) radiation, x-rays, or heavy charged particles have been used to treat pituitary adenomas. The goals of these techniques are similar: the highly precise delivery of conformal radiation to the target pituitary tumor while avoiding exposure to adjacent critical normal structures. In the sellar region, the optic apparatus, the native hypothalamic-pituitary structures, and the adjacent normal cerebrum are of most importance. In order to optimize tumor killing, stereotactic radiosurgery is typically delivered in up to 5 high dose fractions; although conventional fractionation has been used to deliver fractionated stereotactic radiotherapy (FSRT). Fig. 24-4 shows an example of a single fraction radiosurgery isodose plan for a small residual pituitary adenoma involving the right aspect of the sella and right cavernous sinus.

FIGURE 24-4 • A, Radiosurgery isodose plan for residual non-secreting pituitary adenoma: Coronal (A) isodose plan (target tumor outlined in red). Prescription isodose line (green) illustrates a highly conformal dose. B, Rapid dose fall-off illustrated by the 50% (cyan) and 25% (blue) curves.

The prevailing radiobiologic factors that determine the effectiveness of radiosurgery are not well understood. However, the radiosensitivity of secretory pituitary adenomas may be influenced by the administration of antisecretory medications. Landolt et al. were the first to describe a phenomenon a radioprotective effect of antisecretory medications on growth hormone secreting pituitary adenomas and prolactinomas which resulted in lower rates of hormonal control.³⁰^,⁶² These authors hypothesize that radioprotection resulted from a change in the tumor’s metabolic rate induced by the medications. Pollock reported similar findings in a study of 43 patients with hormone-producing pituitary adenomas undergoing radiosurgery.⁶³ Forty-seven percent of patients achieved normalization of hormone secretion at a median time of 14 months. The absence of antisecretory medications at the time of radiosurgery as well as maximum radiation dose >40 Gy were the only factors correlated with cure on multivariate analysis.⁶³ Of note, these studies were all retrospective and did not involve randomization to use of somatostatin analogs at the time of radiation therapy, and it is possible that the somatostatin analog groups reflected patients with more aggressive tumors. At least two groups were unable to replicate these findings with radiosurgery.³¹^,⁴⁵ Nevertheless, it has become widely recommended that antisecretory medications be discontinued for 1 to 2 months before administering radiosurgery.⁶²^,⁶⁴

Stereotactic radiosurgery series have reported growth control rates of more than 95% on average, although few series have median follow-up times beyond 4 years. The endocrinologic control rates have been highly variable, due in part to the variability of definitions of criteria of control. Biochemical control of plasma and urine cortisol levels in Cushing’s disease is reported to be 17% to 83%. Table 24-4 lists selected radiotherapy series of Cushing’s disease with at least five patients and at least 2 years of follow-up.

Table 24-4 Selected Radiosurgery Series of Cushing’s Disease

For acromegaly, it is generally appreciated that normalization of IGF-1 levels is an accurate criterion for cure, though there has been variability in criteria defining biochemical “cure,” such as with use of GH levels. Thus, it is not surprising that reported cure rates vary from 0% to 100%; studies defining the extremes of this range are quite small and may not be representative.⁶⁵^–⁶⁷ Using serum IGF-1 criteria for biochemical response and with relatively limited follow-up, studies involving gamma knife radiosurgery have shown that only a minority of subjects achieve cure without requiring concomitant medical therapy: 17% of 82 subjects followed for a mean of 4 years in one study,³¹ and 17% of 53 patients followed for a mean of 5.5 years.⁸⁴ Table 24-5 lists studies with at least 2-year follow-up that used the criterion of normal IGF-1 as a component of the definition of endocrine cure. The rate of endocrine cure from these sources is 20% to 100%. Radiosurgical cure rates for prolactinoma range from 0% to 84%. Although the rates of normalization of prolactin levels appears low, clinical improvements are observed in a larger number of patients.⁶⁸

Table 24-5 Selected Radiosurgery Series of Acromegaly