Clinical manifestations of sellar lesions vary, depending on the anatomic location of the mass and the direction of its extension (Table 51-1). The dorsal sellar diaphragm presents the least resistance to soft tissue expansion from the sella; consequently, pituitary adenomas frequently extend in a suprasellar direction. Bony invasion may occur as well.
| IMPACTED STRUCTURE | CLINICAL IMPACT |
|---|---|
| Pituitary | Hypogonadism Hypothyroidism Growth failure and adult hyposomatotropism Hypoadrenalism |
| Optic chiasm | Loss of red perception Bitemporal hemianopia Superior or bitemporal field defect Scotoma Blindness |
| Hypothalamus | Temperature dysregulation Appetite and thirst disorders Obesity Diabetes insipidus Sleep disorders Behavioral dysfunction Autonomic dysfunction |
| Cavernous sinus | Ophthalmoplegia with or without ptosis or diplopia Facial numbness |
| Frontal lobe | Personality disorder Anosmia |
| Brain | Headache Hydrocephalus Psychosis Dementia Laughing seizures |
Headaches are common features of small intrasellar tumors, even with no demonstrable suprasellar extension. Because of the confined nature of the pituitary, small changes in intrasellar pressure stretch the dural plate; however, headache severity correlates poorly with adenoma size or extension.
Suprasellar extension can lead to visual loss by several mechanisms, the most common being compression of the optic chiasm, but rarely, direct invasion of the optic nerves or obstruction of cerebrospinal fluid (CSF) flow leading to secondary visual disturbances can occur. Pituitary stalk compression by a hormonally active or inactive intrasellar mass may compress the portal vessels, disrupting pituitary access to hypothalamic hormones and dopamine; this results in early hyperprolactinemia and later concurrent loss of other pituitary hormones. This “stalk section” phenomenon may also be caused by trauma, whiplash injury with posterior clinoid stalk compression, or skull base fractures. Lateral mass invasion may impinge on the cavernous sinus and compress its neural contents, leading to cranial nerve III, IV, and VI palsies as well as effects on the ophthalmic and maxillary branches of the fifth cranial nerve (Chap. 42). Patients may present with diplopia, ptosis, ophthalmoplegia, and decreased facial sensation, depending on the extent of neural damage. Extension into the sphenoid sinus indicates that the pituitary mass has eroded through the sellar floor. Aggressive tumors rarely invade the palate roof and cause nasopharyngeal obstruction, infection, and CSF leakage. Temporal and frontal lobe involvement may rarely lead to uncinate seizures, personality disorders, and anosmia. Direct hypothalamic encroachment by an invasive pituitary mass may cause important metabolic sequelae, including precocious puberty or hypogonadism, diabetes insipidus, sleep disturbances, dysthermia, and appetite disorders.
Sagittal and coronal T1-weighted magnetic resonance imaging (MRI) before and after administration of gadolinium allows precise visualization of the pituitary gland with clear delineation of the hypothalamus, pituitary stalk, pituitary tissue and surrounding suprasellar cisterns, cavernous sinuses, sphenoid sinus, and optic chiasm. Pituitary gland height ranges from 6 mm in children to 8 mm in adults; during pregnancy and puberty, the height may reach 10–12 mm. The upper aspect of the adult pituitary is flat or slightly concave, but in adolescent and pregnant individuals, this surface may be convex, reflecting physiologic pituitary enlargement. The stalk should be midline and vertical. Computed tomography (CT) scan is reserved to define the extent of bony erosion or the presence of calcification.
Anterior pituitary gland soft tissue consistency is slightly heterogeneous on MRI, and signal intensity resembles that of brain matter on T1-weighted imaging (Fig. 51-1). Adenoma density is usually lower than that of surrounding normal tissue on T1-weighted imaging, and the signal intensity increases with T2-weighted images. The high phospholipid content of the posterior pituitary results in a “pituitary bright spot.”
Sellar masses are encountered commonly as incidental findings on MRI, and most of them are pituitary adenomas (incidentalomas). In the absence of hormone hypersecretion, these small intrasellar lesions can be monitored safely with MRI, which is performed annually and then less often if there is no evidence of further growth. Resection should be considered for incidentally discovered larger macroadenomas, because about one-third become invasive or cause local pressure effects. If hormone hypersecretion is evident, specific therapies are indicated as described below. When larger masses (>1 cm) are encountered, they should also be distinguished from nonadenomatous lesions. Meningiomas often are associated with bony hyperostosis; craniopharyngiomas may be calcified and are usually hypodense, whereas gliomas are hyperdense on T2-weighted images.
Because optic tracts may be contiguous to an expanding pituitary mass, reproducible visual field assessment using perimetry techniques should be performed on all patients with sellar mass lesions that impinge the optic chiasm (Chap. 25). Bitemporal hemianopia, often more pronounced superiorly, is observed classically. It occurs because nasal ganglion cell fibers, which cross in the optic chiasm, are especially vulnerable to compression of the ventral optic chiasm. Occasionally, homonymous hemianopia occurs from postchiasmal compression or monocular temporal field loss from prechiasmal compression. Invasion of the cavernous sinus can produce diplopia from ocular motor nerve palsy. Early diagnosis reduces the risk of optic atrophy, vision loss, or eye misalignment.
The presenting clinical features of functional pituitary adenomas (e.g., acromegaly, prolactinomas, or Cushing’s syndrome) should guide the laboratory studies (Table 51-2). However, for a sellar mass with no obvious clinical features of hormone excess, laboratory studies are geared toward determining the nature of the tumor and assessing the possible presence of hypopituitarism. When a pituitary adenoma is suspected based on MRI, initial hormonal evaluation usually includes (1) basal prolactin (PRL); (2) insulin-like growth factor (IGF) I; (3) 24-h urinary free cortisol (UFC) and/or overnight oral dexamethasone (1 mg) suppression test; (4) α subunit, follicle-stimulating hormone (FSH), and luteinizing hormone (LH); and (5) thyroid function tests. Additional hormonal evaluation may be indicated based on the results of these tests. Pending more detailed assessment of hypopituitarism, a menstrual history, measurement of testosterone and 8 A.M. cortisol levels, and thyroid function tests usually identify patients with pituitary hormone deficiencies that require hormone replacement before further testing or surgery.
| TEST | COMMENTS | |
|---|---|---|
| Acromegaly | Serum IGF-I Oral glucose tolerance test with GH obtained at 0, 30, and 60 min | Interpret IGF-I relative to age- and sex-matched controls Normal subjects should suppress growth hormone to <1 g/L |
| Prolactinoma | Serum PRL | Exclude medications MRI of the sella should be ordered if PRL is elevated |
| Cushing’s disease | 24-h urinary free cortisol Dexamethasone (1 mg) at 11 P.M. and fasting plasma cortisol measured at 8 A.M. ACTH assay | Ensure urine collection is total and accurate Normal subjects suppress to <5 g/dL Distinguishes adrenal adenoma (ACTH suppressed) from ectopic ACTH or Cushing’s disease (ACTH normal or elevated) |
Immunohistochemical staining of pituitary tumor specimens obtained at transsphenoidal surgery confirms clinical and laboratory studies and provides a histologic diagnosis when hormone studies are equivocal and in cases of clinically nonfunctioning tumors. Occasionally, ultrastructural assessment by electron microscopy is required for diagnosis.
TREATMENT: Hypothalamic, Pituitary, and Other Sellar Masses OVERVIEW
Successful management of sellar masses requires accurate diagnosis as well as selection of optimal therapeutic modalities. Most pituitary tumors are benign and slow-growing. Clinical features result from local mass effects and hormonal hyper- or hyposecretion syndromes caused directly by the adenoma or occurring as a consequence of treatment. Thus, lifelong management and follow-up are necessary for these patients.
MRI with gadolinium enhancement for pituitary visualization, new advances in transsphenoidal surgery and in stereotactic radiotherapy (including gamma-knife radiotherapy), and novel therapeutic agents have improved pituitary tumor management. The goals of pituitary tumor treatment include normalization of excess pituitary secretion, amelioration of symptoms and signs of hormonal hypersecretion syndromes, and shrinkage or ablation of large tumor masses with relief of adjacent structure compression. Residual anterior pituitary function should be preserved during treatment and sometimes can be restored by removing the tumor mass. Ideally, adenoma recurrence should be prevented.
TRANSSPHENOIDAL SURGERYTranssphenoidal rather than transfrontal resection is the desired surgical approach for pituitary tumors, except for the rare invasive suprasellar mass surrounding the frontal or middle fossa or the optic nerves or invading posteriorly behind the clivus. Intraoperative microscopy facilitates visual distinction between adenomatous and normal pituitary tissue as well as microdissection of small tumors that may not be visible by MRI (Fig. 51-2). Transsphenoidal surgery also avoids the cranial invasion and manipulation of brain tissue required by subfrontal surgical approaches. Endoscopic techniques with three-dimensional intraoperative localization have also improved visualization and access to tumor tissue. Individual surgical experience is a major determinant of outcome efficacy with these techniques.
In addition to correction of hormonal hypersecretion, pituitary surgery is indicated for mass lesions that impinge on surrounding structures. Surgical decompression and resection are required for an expanding pituitary mass accompanied by persistent headache, progressive visual field defects, cranial nerve palsies, hydrocephalus, and, occasionally, intrapituitary hemorrhage and apoplexy. Transsphenoidal surgery sometimes is used for pituitary tissue biopsy to establish a histologic diagnosis.Whenever possible, the pituitary mass lesion should be selectively excised; normal pituitary tissue should be manipulated or resected only when critical for effective mass dissection. Nonselective hemihypophysectomy or total hypophysectomy may be indicated if no hypersecreting mass lesion is clearly discernible, multifocal lesions are present, or the remaining nontumorous pituitary tissue is obviously necrotic. This strategy, however, increases the likelihood of hypopituitarism and the need for lifelong hormone replacement.
Preoperative mass effects, including visual field defects and compromised pituitary function, may be reversed by surgery, particularly when the deficits are not long-standing. For large and invasive tumors, it is necessary to determine the optimal balance between maximal tumor resection and preservation of anterior pituitary function, especially for preserving growth and reproductive function in younger patients. Similarly, tumor invasion outside the sella is rarely amenable to surgical cure; the surgeon must judge the risk-versus-benefit ratio of extensive tumor resection.
Side effectsTumor size, the degree of invasiveness, and experience of the surgeon largely determine the incidence of surgical complications. Operative mortality rate is about 1%. Transient diabetes insipidus and hypopituitarism occur in up to 20% of patients. Permanent diabetes insipidus, cranial nerve damage, nasal septal perforation, or visual disturbances may be encountered in up to 10% of patients. CSF leaks occur in 4% of patients. Less common complications include carotid artery injury, loss of vision, hypothalamic damage, and meningitis. Permanent side effects are rare after surgery for microadenomas.
RADIATIONRadiation is used either as a primary therapy for pituitary or parasellar masses or, more commonly, as an adjunct to surgery or medical therapy. Focused megavoltage irradiation is achieved by precise MRI localization, using a high-voltage linear accelerator and accurate isocentric rotational arcing. A major determinant of accurate irradiation is reproduction of the patient’s head position during multiple visits and maintenance of absolute head immobility. A total of <50 Gy (5000 rad) is given as 180-cGy (180-rad) fractions divided over about 6 weeks. Stereotactic radiosurgery delivers a large single high-energy dose from a cobalt-60 source (gamma knife), linear accelerator, or cyclotron. Long-term effects of gamma-knife surgery are unclear but appear to be similar to those encountered with conventional radiation. Proton beam therapy is available in some centers and provides concentrated radiation doses within a localized region.
The role of radiation therapy in pituitary tumor management depends on multiple factors, including the nature of the tumor, the age of the patient, and the availability of surgical and radiation expertise. Because of its relatively slow onset of action, radiation therapy is usually reserved for postsurgical management. As an adjuvant to surgery, radiation is used to treat residual tumor and in an attempt to prevent regrowth. Irradiation offers the only means for potentially ablating significant postoperative residual nonfunctioning tumor tissue. In contrast, PRL- and growth hormone (GH)-secreting tumor tissues are amenable to medical therapy.
Side effectsIn the short term, radiation may cause transient nausea and weakness. Alopecia and loss of taste and smell may be more long-lasting. Failure of pituitary hormone synthesis is common in patients who have undergone head and neck or pituitary-directed irradiation. More than 50% of patients develop loss of GH, adrenocorticotropin hormone (ACTH), thyroid-stimulating hormone (TSH), and/or gonadotropin secretion within 10 years, usually due to hypothalamic damage. Lifelong follow-up with testing of anterior pituitary hormone reserve is therefore required after radiation treatment. Optic nerve damage with impaired vision due to optic neuritis is reported in about 2% of patients who undergo pituitary irradiation. Cranial nerve damage is uncommon now that radiation doses are ≤2 Gy (200 rad) at any one treatment session and the maximum dose is <50 Gy (5000 rad). The use of stereotactic radiotherapy may reduce damage to adjacent structures. Radiotherapy for pituitary tumors has been associated with adverse mortality rates, mainly from cerebrovascular disease. The cumulative risk of developing a secondary tumor after conventional radiation is 1.3% after 10 years and 1.9% after 20 years.
MEDICALMedical therapy for pituitary tumors is highly specific and depends on tumor type. For prolactinomas, dopamine agonists are the treatment of choice. For acromegaly, somatostatin analogues and GH receptor antagonists are indicated. For TSH-secreting tumors, somatostatin analogues and occasionally dopamine agonists are indicated. ACTH-secreting tumors and nonfunctioning tumors are generally not responsive to medications and require surgery and/or irradiation.
Sellar masses other than pituitary adenomas may arise from brain, hypothalamic, or pituitary tissues. Each exhibit features related to the lesion location but also unique to the specific etiology.
Lesions involving the anterior and preoptic hypothalamic regions cause paradoxical vasoconstriction, tachycardia, and hyperthermia. Acute hyperthermia usually is due to a hemorrhagic insult, but poikilothermia may also occur. Central disorders of thermoregulation result from posterior hypothalamic damage. The periodic hypothermia syndrome is characterized by episodic attacks of rectal temperatures <30°C (86°F), sweating, vasodilation, vomiting, and bradycardia. Damage to the ventromedial hypothalamic nuclei by craniopharyngiomas, hypothalamic trauma, or inflammatory disorders may be associated with hyperphagia and obesity. This region appears to contain an energy-satiety center where melanocortin receptors are influenced by leptin, insulin, pro-opiomelanocortin (POMC) products, and gastrointestinal peptides. Polydipsia and hypodipsia are associated with damage to central osmoreceptors located in preoptic nuclei (Chap. 52). Slow-growing hypothalamic lesions can cause increased somnolence and disturbed sleep cycles as well as obesity, hypothermia, and emotional outbursts. Lesions of the central hypothalamus may stimulate sympathetic neurons, leading to elevated serum catecholamine and cortisol levels. These patients are predisposed to cardiac arrhythmias, hypertension, and gastric erosions.
Craniopharyngiomas are benign, suprasellar cystic masses that present with headaches, visual field deficits, and variable degrees of hypopituitarism. They are derived from Rathke’s pouch and arise near the pituitary stalk, commonly extending into the suprasellar cistern. Craniopharyngiomas are often large, cystic, and locally invasive. Many are partially calcified, exhibiting a characteristic appearance on skull x-ray and CT images. More than half of all patients present before age 20, usually with signs of increased intracranial pressure, including headache, vomiting, papilledema, and hydrocephalus. Associated symptoms include visual field abnormalities, personality changes and cognitive deterioration, cranial nerve damage, sleep difficulties, and weight gain. Hypopituitarism can be documented in about 90%, and diabetes insipidus occurs in about 10% of patients. About half of affected children present with growth retardation. MRI is generally superior to CT for evaluating cystic structure and tissue components of craniopharyngiomas. CT is useful to define calcifications and evaluate invasion into surrounding bony structures and sinuses.
Treatment usually involves transcranial or transsphenoidal surgical resection followed by postoperative radiation of residual tumor. Surgery alone is curative in less than half of patients because of recurrences due to adherence to vital structures or because of small tumor deposits in the hypothalamus or brain parenchyma. The goal of surgery is to remove as much tumor as possible without risking complications associated with efforts to remove firmly adherent or inaccessible tissue. In the absence of radiotherapy, about 75% of craniopharyngiomas recur, and 10-year survival is less than 50%. In patients with incomplete resection, radiotherapy improves 10-year survival to 70–90% but is associated with increased risk of secondary malignancies. Most patients require lifelong pituitary hormone replacement.
Developmental failure of Rathke’s pouch obliteration may lead to Rathke’s cysts, which are small (<5 mm) cysts entrapped by squamous epithelium and are found in about 20% of individuals at autopsy. Although Rathke’s cleft cysts do not usually grow and are often diagnosed incidentally, about a third present in adulthood with compressive symptoms, diabetes insipidus, and hyperprolactinemia due to stalk compression. Rarely, hydrocephalus develops. The diagnosis is suggested preoperatively by visualizing the cyst wall on MRI, which distinguishes these lesions from craniopharyngiomas. Cyst contents range from CSF-like fluid to mucoid material. Arachnoid cysts are rare and generate an MRI image that is isointense with CSF.
Sella chordomas usually present with bony clival erosion, local invasiveness, and, on occasion, calcification. Normal pituitary tissue may be visible on MRI, distinguishing chordomas from aggressive pituitary adenomas. Mucinous material may be obtained by fine-needle aspiration.
Meningiomas arising in the sellar region may be difficult to distinguish from nonfunctioning pituitary adenomas. Meningiomas typically enhance on MRI and may show evidence of calcification or bony erosion. Meningiomas may cause compressive symptoms.
Histiocytosis X includes a variety of syndromes associated with foci of eosinophilic granulomas. Diabetes insipidus, exophthalmos, and punched-out lytic bone lesions (Hand-Schüller-Christian disease) are associated with granulomatous lesions visible on MRI, as well as a characteristic axillary skin rash. Rarely, the pituitary stalk may be involved.
Pituitary metastases occur in ~3% of cancer patients. Bloodborne metastatic deposits are found almost exclusively in the posterior pituitary. Accordingly, diabetes insipidus can be a presenting feature of lung, gastrointestinal, breast, and other pituitary metastases. About half of pituitary metastases originate from breast cancer; about 25% of patients with metastatic breast cancer have such deposits. Rarely, pituitary stalk involvement results in anterior pituitary insufficiency. The MRI diagnosis of a metastatic lesion may be difficult to distinguish from an aggressive pituitary adenoma; the diagnosis may require histologic examination of excised tumor tissue. Primary or metastatic lymphoma, leukemias, and plasmacytomas also occur within the sella.
Hypothalamic hamartomas and gangliocytomas may arise from astrocytes, oligodendrocytes, and neurons with varying degrees of differentiation. These tumors may overexpress hypothalamic neuropeptides, including gonadotropin-releasing hormone (GnRH), growth hormone–releasing hormone (GHRH), and corticotropin-releasing hormone (CRH). With GnRH-producing tumors, children present with precocious puberty, psychomotor delay, and laughing-associated seizures. Medical treatment of GnRH-producing hamartomas with long-acting GnRH analogues effectively suppresses gonadotropin secretion and controls premature pubertal development. Rarely, hamartomas also are associated with craniofacial abnormalities; imperforate anus; cardiac, renal, and lung disorders; and pituitary failure as features of Pallister-Hall syndrome, which is caused by mutations in the carboxy terminus of the GLI3 gene. Hypothalamic hamartomas are often contiguous with the pituitary, and preoperative MRI diagnosis may not be possible. Histologic evidence of hypothalamic neurons in tissue resected at transsphenoidal surgery may be the first indication of a primary hypothalamic lesion.
Hypothalamic gliomas and optic gliomas occur mainly in childhood and usually present with visual loss. Adults have more aggressive tumors; about a third are associated with neurofibromatosis.
Brain germ cell tumors may arise within the sellar region. They include dysgerminomas, which frequently are associated with diabetes insipidus and visual loss. They rarely metastasize. Germinomas, embryonal carcinomas, teratomas, and choriocarcinomas may arise in the parasellar region and produce hCG. These germ cell tumors present with precocious puberty, diabetes insipidus, visual field defects, and thirst disorders. Many patients are GH-deficient with short stature.
Pituitary adenomas are the most common cause of pituitary hormone hypersecretion and hyposecretion syndromes in adults. They account for ~15% of all intracranial neoplasms and have been identified with a population prevalence of ~80/100,000. At autopsy, up to one-quarter of all pituitary glands harbor an unsuspected microadenoma (<10 mm diameter). Similarly, pituitary imaging detects small clinically inapparent pituitary lesions in at least 10% of individuals.
Pituitary adenomas are benign neoplasms that arise from one of the five anterior pituitary cell types. The clinical and biochemical phenotypes of pituitary adenomas depend on the cell type from which they are derived. Thus, tumors arising from lactotrope (PRL), somatotrope (GH), corticotrope (ACTH), thyrotrope (TSH), or gonadotrope (LH, FSH) cells hypersecrete their respective hormones (Table 51-3). Plurihormonal tumors express various combinations of GH, PRL, TSH, ACTH, or the glycoprotein hormone α or β subunits. They may be diagnosed by careful immunocytochemistry or may manifest as clinical syndromes that combine features of these hormonal hypersecretory syndromes. Morphologically, these tumors may arise from a single polysecreting cell type or include cells with mixed function within the same tumor.
| ADENOMA CELL ORIGIN | HORMONE PRODUCT | CLINICAL SYNDROME |
|---|---|---|
| Lactotrope | PRL | Hypogonadism, galactorrhea |
| Gonadotrope | FSH, LH, subunits | Silent or hypogonadism |
| Somatotrope | GH | Acromegaly/gigantism |
| Corticotrope | ACTH | Cushing’s disease |
| Mixed growth hormone and prolactin cell | GH, PRL | Acromegaly, hypogonadism, galactorrhea |
| Other plurihormonal cell | Any | Mixed |
| Acidophil stem cell | PRL, GH | Hypogonadism, galactorrhea, acromegaly |
| Mammosomatotrope | PRL, GH | Hypogonadism, galactorrhea, acromegaly |
| Thyrotrope | TSH | Thyrotoxicosis |
| Null cell | None | Pituitary failure |
| Oncocytoma | None | Pituitary failure |
Hormonally active tumors are characterized by autonomous hormone secretion with diminished feedback responsiveness to physiologic inhibitory pathways. Hormone production does not always correlate with tumor size. Small hormone-secreting adenomas may cause significant clinical perturbations, whereas larger adenomas that produce less hormone may be clinically silent and remain undiagnosed (if no central compressive effects occur). About one-third of all adenomas are clinically nonfunctioning and produce no distinct clinical hypersecretory syndrome. Most of them arise from gonadotrope cells and may secrete small amounts of α- and β-glycoprotein hormone subunits or, very rarely, intact circulating gonadotropins. True pituitary carcinomas with documented extracranial metastases are exceedingly rare.
Almost all pituitary adenomas are monoclonal in origin, implying the acquisition of one or more somatic mutations that confer a selective growth advantage. Consistent with their clonal origin, complete surgical resection of small pituitary adenomas usually cures hormone hypersecretion. Nevertheless, hypothalamic hormones such as GHRH and CRH also enhance mitotic activity of their respective pituitary target cells in addition to their role in pituitary hormone regulation. Thus, patients who harbor rare abdominal or chest tumors that elaborate ectopic GHRH or CRH may present with somatotrope or corticotrope hyperplasia with GH or ACTH hypersecretion.
Several etiologic genetic events have been implicated in the development of pituitary tumors. The pathogenesis of sporadic forms of acromegaly has been particularly informative as a model of tumorigenesis. GHRH, after binding to its G protein–coupled somatotrope receptor, uses cyclic adenosine monophosphate (AMP) as a second messenger to stimulate GH secretion and somatotrope proliferation. A subset (~35%) of GH-secreting pituitary tumors contains sporadic mutations in Gsα (Arg 201 → Cys or His; Gln 227 → Arg). These mutations attenuate intrinsic GTPase activity, resulting in constitutive elevation of cyclic AMP, Pit-1 induction, and activation of cyclic AMP response element binding protein (CREB), thereby promoting somatotrope cell proliferation and GH secretion.
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