Pituitary Tumors and Craniopharyngiomas

Etiology

Although the etiology of most pituitary tumors is not fully understood, four human genes are known to be associated with familial pituitary tumor syndromes: multiple endocrine neoplasia (MEN) 1; cyclin dependent kinase inhibitor (CDKN) 1B; protein kinase, cAMP-dependent, regulatory (PRKAR) 1A; and aryl hydrocarbon receptor-interacting protein (AIP). For patients with MEN1, which is an autosomal-dominant disease, 40% will develop pituitary adenomas, most commonly prolactinomas. In Carney's complex, a rare inherited condition characterized by endocrine overactivity, schwannomas, abnormal skin pigmentation, and myxomas, the implicated genetic defect is loss of function of PRKAR1A, whose gene is located on chromosome 17q23-24. Patients with McCune-Albright syndrome demonstrate mosaicism, resulting from a postzygotic somatic mutation appearing early in the course of development that yields a monoclonal population of mutated cells within variously affected tissues. In isolated familial somatotropinomas, germline alterations in the aryl hydrocarbon receptor interacting gene ( AIP gene) have been identified.

No causal relationship has been identified between pituitary adenomas and factors such as cigarette smoking, past history of head trauma, or prior neoplasms.

Epidemiology

Pituitary tumors represent one of the most common primary intracranial tumors. In the United States, pituitary tumors increase in incidence with age and are more frequent in females and African-Americans. Community-based studies from Belgium and the United Kingdom suggest that the prevalence is higher than has been historically noted. Based on a meta-analysis, the overall estimated prevalence of pituitary adenomas was 16.7%, with 14.4% observed in autopsy series and 22.5% in radiographic series of volunteers or patients imaged for other diseases. Pediatric pituitary tumors are very uncommon in children and adolescents and are more invasive than previously predicted.

The frequency of the various types of pituitary adenomas differs widely according to age and gender. Prolactinomas are the most common, followed by nonfunctioning adenomas, growth hormone (GH)–secreting adenomas, and adrenocorticotropic hormone (ACTH)–secreting adenomas. Thyroid-stimulating hormone (TSH)–secreting adenomas are rare. Pituitary carcinomas are extremely rare.

Prevention and Early Detection

No successful strategy is known to prevent the development of these tumors. Given the prevalence of pituitary abnormalities on magnetic resonance imaging (MRI) scans in normal adult patients, the routine use of screening MRI or endocrine workup is not recommended. When imaging is performed not specifically for a pituitary lesion, an incidental finding of a pituitary lesion, the so-called “incidentaloma,” may be diagnosed in upward of 20% of computed tomography (CT) scans and 38% of MRI scans with the majority being pituitary adenomas or Rathke's cleft cysts. Although most incidentalomas are less than 1 cm and nonfunctional, they may be associated with pituitary hormonal deficiencies, excess hormone secretion, or visual field defects. . Based on autopsy series, pituitary incidentaloma occurs in only 1.5% of children and adolescents.

Any patient with signs or symptoms suggestive of an endocrine abnormality should be referred to an endocrinologist. Consultation with an endocrinologist and a medical geneticist is appropriate for patients if MEN1 or another familial syndrome associated with pituitary adenoma is suspected. For these patients, a baseline MRI of the pituitary can be considered, although routine imaging is not uniformly performed. The management of inherited pituitary tumors is usually similar to that of sporadic adenomas.

Anatomy and Pathways of Spread

The pituitary gland is a midline intracranial organ that occupies the cavity in the sphenoid bone known as the sella turcica. The pituitary gland is separated from the structures above it (i.e., the optic chiasm, hypothalamus, anterior cerebral arteries, and floor of the third ventricle) by the diaphragm sellae. Immediately anterosuperior to the diaphragma sellae lies the optic chiasm. The pituitary stalk (infundibulum) crosses the diaphragma sellae and connects the hypothalamus to the pituitary gland. Anteriorly, the tuberculum sellae is the midline bone that forms the anterior margin of the sella turcica and extending superolaterally to the anterior clinoid processes forms the lateral margin of the optic canals. Posteriorly, the dorsum sellae is the midline bone that forms the posterior margin of the sella turcica and extends superolaterally to form the posterior clinoid processes. Laterally, the cavernous sinuses contain cranial nerves III, IV, V ₁ (ophthalmic nerve), V ₂ (maxillary nerve), and VI, and the internal carotid artery. Given the proximity of the pituitary to these various structures, parasellar tumors can affect these cranial nerves, and suprasellar tumor extension can lead to bitemporal hemianopsia via compression of the optic chiasm. Fig. 34.1 demonstrates the complex anatomy of the sellar and parasellar region.

The pituitary has two distinct embryologic origins; the first gives rise to the anterior and intermediate pituitary lobes and the second gives rise to the posterior pituitary lobe. The anterior (adenohypophysis) and intermediate lobes are derived from Rathke's pouch. The posterior lobe (neurohypophysis) and stalk are derived from the diencephalon. The anterior pituitary lobe accounts for most of the pituitary gland and produces six hormones: prolactin (PRL), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH), and thyroid-stimulating hormone (TSH). The intermediate lobe produces melanocyte-stimulating hormone (MSH). The posterior lobe stores and releases two hormones, vasopressin (antidiuretic hormone [ADH]) and oxytocin, which are produced by the hypothalamus.

Pituitary tumors are generally classified depending on the diameter of the tumor. A microadenoma is less than 1 cm in diameter, whereas a macroadenoma has a diameter of 1 cm or greater. Microadenomas are more frequently seen in females, whereas macroadenomas occur with equal frequency in males and females. For lesions less than 3 mm in diameter, the term picoadenoma has been used. Pituicytoma, a rare low-grade glial neoplasm that originates in the distribution of the neurohypophysis, can be misdiagnosed preoperatively as a pituitary adenoma.

Pathology

Historically, pituitary tumors were classified according to Mallory's trichrome histologic staining technique as chromophobic, acidophilic (or eosinophilic), or basophilic tumors. With newer methods of immunostaining, cells were identified as prolactin, ACTH, GH, LH, FSH, alpha subunit, or TSH. The 2017 World Health Organization (WHO) classification is mostly based on immunohistochemistry for pituitary hormones, pituitary-specific transcription factors, and other immunohistochemistry markers not requiring routine ultrastructural analysis of the tumor; it also includes a novel approach for classifying pituitary neuroendocrine tumors according to adenohypophyseal cell lineages. Although no routine ultrastructural analysis of the tumors is now required, evaluation of tumor proliferation potential by mitotic count and/or Ki-67 labeling, as well as identification of tumor invasion, are strongly recommended. To help identify clinically aggressive adenomas, mitotic count and Ki-67 labeling index are strongly recommended.

The revised classification introduces more precise cell lineage-based classification of pituitary adenoma that is defined by transcription factors and hormones produced. Hormone-producing adenoma is now abandoned in favor of pituitary adenohypophyseal cell lineage. The classification includes a new entity designating a borderline adenoma or adenoma of uncertain behavior. Also historically, “atypical adenoma” was defined as an invasive tumor with an elevated mitotic index -1-labeling index greater than 3%) and extensive nuclear immunostaining for p53. The recent WHO classification removed atypical adenoma and introduced new entities, such as pituitary blastoma, which appears to be a pediatric and DICER1-specific tumor.

For functioning pituitary macroadenomas, MGMT (O6-methyl-guanine-DNA methyltransferase) and MSH6 (mutS homolog 6) immunoexpression have been linked to the response to temozolomide treatment and MGMT immunoexpression has been associated with early recurrence of nonfunctioning pituitary adenomas.

Clinical Manifestations

Patients with pituitary tumors can have a number of different symptoms and presentations, depending on the size and mass effect of the tumor and hormonal abnormalities, and age and gender of the patient. When the tumor extends superiorly into the suprasellar region, visual loss can occur, including bitemporal or homonymous hemianopsia, superior or inferior field cut deficits, and central scotoma. Extension into the cavernous sinus can lead to cranial nerve dysfunction (commonly IIIrd and IVth cranial nerve palsies). Lateral extension into the temporal lobe may cause seizures. Patients with large adenomas may have compromised pituitary function, which can lead to secondary hypogonadism, secondary hypothyroidism, and secondary adrenal insufficiency. Diabetes insipidus is extremely rare and most commonly is a manifestation of an invasive and infiltrative tumor (e.g., a metastasis). If the gland acutely infarcts or hemorrhages, pituitary apoplexy may result and may require urgent surgical decompression.

Patient Evaluation

Laboratory Assessment

Initial tests help determine if a pituitary deficiency exists and diagnose the secretory status of the adenoma. Screening studies should include TSH, free thyroxine (T ₄ ), ACTH, cortisol, prolactin, somatomedin C (insulin-like growth factor-1 [IGF-1] because this is the primary molecule mediating the effects of growth hormone at the cellular level, and its secretion, primarily from the liver, is directly regulated by growth hormone), LH, FSH, alpha subunit, and, in men, testosterone.

In addition, a complete blood count, blood chemistry assessment, and urinalysis should be obtained. Because physiologic hormonal variations in the blood and urine levels can occur, the interpretation of these results should be considered based on diurnal variations, age and gender of the patient, and pregnancy and menopausal status. The conditions and timing under which these samples are obtained also influence interpretations of the results. Because the diagnosis of Cushing disease can be difficult, multiple tests are performed over time and at different times during the day to help make a conclusive diagnosis.

For patients with suspected Cushing disease, 24-hour urinary free cortisol, midnight salivary cortisol, and 1-mg overnight dexamethasone suppression tests have similar sensitivity and specificity. The most precise method of measurement for 24-hour urinary free cortisol is tandem mass spectrometry. The overnight dexamethasone suppression test may be influenced by several medications and requires specific time constraints. As a result, this test should not be used as the sole test for diagnosing Cushing syndrome. When ACTH-dependent hypercortisolism has been diagnosed, an MRI is performed. In patients with large microadenomas or macroadenomas, Cushing disease is diagnosed. If the MRI is negative or shows a small abnormality, the definitive test for Cushing disease and exclusion of ectopic ACTH syndrome is inferior petrosal sinus sampling. This test requires measurement of ACTH from the right and left petrosal sinuses and peripheral site before and after corticotropin-releasing hormone administration.

For patients with prolactinoma who also have macroadenoma, the prolactin level is usually greater than 200 ng/mL. Other common conditions that have been associated with hyperprolactinemia include end-stage renal disease, renal insufficiency, depression, primary hypothyroidism, acquired immunodeficiency syndrome, sarcoidosis, and nonalcoholic cirrhosis. Pituitary stalk compression from a tumor may also cause elevated prolactin levels in the range of 150 ng/mL or less. Because some medications may elevate prolactin levels, careful review of the medications that the patient is taking is necessary. A pregnancy test is mandatory for women with amenorrhea or hyperprolactinemia. Elevated serum prolactin levels greater than 300 ng/mL are usually diagnostic of a prolactinoma, and levels greater than 100 ng/mL in nonpregnant patients often are associated with pituitary adenoma.

Most cases of acromegaly result from excess secretion of growth hormone by a pituitary tumor. The definitive test is measurement of growth hormone response to 75 g or 100 g of oral glucose (oral glucose tolerance test). This glucose load should normally cause marked suppression of the GH release to a level under 2 ng/mL. To ensure accuracy, these measurements of serum glucose and GH must be performed every 30 minutes for 2 hours. IGF-1 levels provide the best intermittent method for monitoring response to treatment, although dynamic testing of GH kinetics with the oral glucose tolerance test is also frequently used.

Mild hyperprolactinemia (< 200 ng/mL) may be seen in some patients with nonfunctional adenomas because this is a common finding when any sellar mass causes stalk compression, thereby interrupting blood flow and leading to interference with the prolactin-inhibiting dopamine transport. Because these patients typically do not have hormone-related symptoms, nonfunctioning adenomas can be quite large at the time of diagnosis.

Imaging

Dynamic MRI of the brain with gadolinium is the imaging test of choice given its superior resolution compared with CT, which evaluates calcifications and bony changes better than MRI ( Fig. 34.2 ). Dynamic coronal imaging techniques after contrast administration enhance normal pituitary tissue earlier and more intensely and help delineate adenoma tissue, which tends to enhance later. Because pituitary adenomas are less vascular than the normal pituitary gland, they usually appear hypointense following gadolinium administration, in the early or in the immediate postgadolinium phase, and later may either remain hypointense, hyperintense, or isointense to the rest of the gland, emphasizing the need for dynamic MRI. On noncontrast T1-weighted MRIs they may appear hypointense or isointense to the normal pituitary gland. The posterior lobe of the pituitary has a high signal intensity on T1-weighted images (posterior pituitary bright spot) that distinguishes it from the anterior lobe, which has a signal intensity similar to that of white matter. Thin slices (at 2-mm to 3-mm intervals) obtained before and after gadolinium contrast administration with images in the coronal, axial, and sagittal planes provide detailed information for the initial diagnosis, allow detection of small lesions, and minimize false– negative rates, which are as high as 45% to 62% with conventional T1-weighted MRI. For patients who have undergone previous surgery, fat suppression techniques can help differentiate surgical fat grafts from tumor tissue. For patients undergoing stereotactic radiosurgery (SRS), thin-slice (1-mm) imaging with contrast is obtained to define the tumor and optic apparatus.

For hypersecretory adenomas, positron emission tomography (PET) imaging with coregistration may be valuable. For acromegalic patients, the use of 11C-methionine PET coregistered with 3D gradient echo MRI (Met-PET/MRI) was investigated in 26 patients with persistent acromegaly after previous treatment, in whom MRI appearances were considered indeterminate. Met-PET/MRI localized sites of abnormal tracer uptake in all but one case, which allowed 14 patients to undergo endoscopic surgery which led to a marked improvement in ( n = 7) or complete resolution of ( n = 7) residual acromegaly. For patients with microadenomas, C-Met PET/CT can provide valuable diagnostic information when fluorodeoxyglucose (FDG) PET/CT yields negative results, especially in patients with recurrent microadenomas.

For patients with suspected Cushing disease, thin-slice images of 1-mm thickness have greater sensitivity; even so, the tumor may not be detected in about 50% of patients. Spoiled gradient recalled acquisition sequences may have superior sensitivity (80%) compared with conventional spin echo images following contrast enhancement. Alternatively, construction interference in steady state (CISS) sequences may augment sensitivity of tumor detection in conjunction with standard sequences.

Macroadenomas can compress the adjacent pituitary and may distort the pituitary stalk. When larger lesions demonstrate extrasellar extension, MRI scans can help delineate the relationship of the cavernous sinus laterally and the optic chiasm superiorly. In order to determine whether cavernous sinus invasion is present, CISS sequences have been shown to better characterize the degree of cavernous sinus invasion compared with T1 after contrast imaging. If a plane of normal pituitary tissue can be observed on coronal T1-contrast enhanced or CISS images, the likelihood of cavernous sinus involvement is extraordinarily low.

Imaging studies other than MRI may be needed. High-resolution CT may be used when MRI is contraindicated (e.g., presence of a pacemaker). CT scans can be useful when planning for transsphenoidal surgery. Pneumatization of the sphenoid sinus and cortical thinning of the sellar floor can be determined by bone windows. Angiograms are useful when aneurysms are suspected.

Differential diagnosis of a sellar lesion includes pituitary adenoma, craniopharyngioma, congenital lesions (Rathke's cleft cyst), infiltrative disease (granuloma, lymphocytic hypophysitis, and tuberculosis), primary lymphoma, chordoma, germ cell tumor, metastases, arachnoid cysts, aneurysm, inflammatory lesions, and meningiomas.

Serial MRI should be performed on a regular basis to detect tumor recurrence. Following SRS or radiation therapy, the initial scan should be obtained 6 months after treatment and then yearly.

Staging

Classification of detectable or symptomatic pituitary tumors can be based on clinical presentation, anatomic extent of disease, and degree of endocrine dysfunction. These tumors can also be broadly classified as functional or nonfunctional based on their secretory activity. As adenomas enlarge, they can extend into suprasellar, parasellar, or infrasellar structures such as the sphenoid sinus. To aid with surgical and imaging assessment, Hardy and Verzina developed a classification system. Wilson's modification of this classification system incorporates imaging and intraoperative findings of sellar destruction (grade) and extrasellar extension (stage). Giant adenomas, which represent 6% to 10% of cases, are defined as a lesion greater than or equal to 4 cm in largest diameter. More recently, the Knosp grading system, which was devised to predict presence of cavernous sinus invasion, has been subdivided to incorporate endoscopic endonasal transsphenoidal verification. A low rate of cavernous invasion was noted with grade 1 adenomas and significantly lower rates of invasion in grade 2 and 3 adenomas than those previously found using the microscopic technique.

General Strategies

The primary objectives of therapy include removal or control of the tumor mass effect, reversal of neurologic symptoms, and reversal of hormonal hypersecretion, while minimizing potential morbidity such as hypopituitarism. Modern surgical approaches, medical management, and innovative radiation techniques have improved the likelihood of accomplishing these goals. The recommendations for treatment are influenced primarily by the type of pituitary tumor and extent of disease.