Hypothalamic Tumor

HYPOTHALAMIC, PITUITARY, AND OTHER SELLAR MASSES

PITUITARY TUMORS

   Pituitary adenomas are the most common cause of pituitary hormone hypersecretion and hyposecretion syndromes in adults. They account for ~15% of all intracranial neoplasms. At autopsy, up to one-quarter of all pituitary glands harbor an unsuspected microadenoma.

Pathogenesis

   Pituitary adenomas are benign neoplasms that arise from one of the five anterior pituitary cell types. The clinical and biochemical phenotype 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. . Plurihormonal tumors that express combinations of GH, PRL, TSH, ACTH, and the glycoprotein hormone α subunit 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 comprise cells with mixed function within the same tumor.

   Hormonally active tumors are characterized by autonomous hormone secretion with diminished 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 these arise from gonadotrope cells and may secrete small amounts of α- and β-glycoprotein hormone sub-units or, very rarely, intact circulating gonadotropins. True pituitary carcinomas with documented extracranial metastases are exceedingly rare.

Classification of Pituitary Adenomas:

Adenoma Gel Organ	Hormone Product	Clinical Syndrome
Lactotrope	PRL	Hypogonadism, galactorrhea
Gonadotrope	FSH, LH, Subunit	Silent or hypogonadism
Somatotrope	GH	Acromegaly/ gigantism
Corticotrope	ACTH	Cushing’s disease
Mixed growth hormone and prolactin cell	GH, PRL	Acromegaly, hypogonadism, galactorrhea
Other plurihormone cell	Any	Mixed
Acidophil stem cell	PRL, GH	Acromegaly, hypogonadism, galactorrhea
Mammosomatotrope	PRL, GH	Acromegaly, hypogonadism, galactorrhea
Thyrotrope	TSH	Thyrotoxicosis
Null cell	None	Pituitary failure
Oncocytoma	None	Pituitary failure

Almost all pituitary adenomas are monoclonal in origin, implying the acquisition of one or more somatic mutations that confer a selective growth advantage. In addition to direct studies of oncogene mutations, this model is supported by X-chromosomal inactivation analyses of tumors in female patients heterozygous for X-linked genes. Consistent with their clonal origin, complete surgical resection of small pituitary adenomas usually cures hormone hypersecretion. Nevertheless, hypothalamic hormones, such as GHRH or CRH, also enhance mitotic activity of their respective pituitary target cells, in addition to their role in pituitary hormone regulation. Thus, patients harboring rare abdominal or chest tumors elaborating ectopic GHRH or CRH may present with somatotrope or corticotrope hyperplasia.

   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, utilizes cyclic AMP as a second messenger to stimulate GH secretion and somatotrope proliferation. A subset (~35%) of GH-secreting pituitary tumors contain sporadic mutations in Gs α (Arg 201 → Cys or His; Gln 227 → Arg).These mutations inhibit 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.

Characteristic loss of heterozygosity (LOH) in various chromosomes has been documented in large or invasive macroadenomas, suggesting the presence of putative tumor suppressor genes at these loci. LOH of chromosome regions on 11q13, 13, and 9 is present in up to 20% of sporadic pituitary tumors including GH-, PRL-, and ACTH-producing adenomas and in some nonfunctioning tumors.

   Compelling evidence also favors growth factor promotion of pituitary tumor proliferation. Basic fibroblast growth factor (bFGF) is abundant in the pituitary and has been shown to stimulate pituitary cell mitogenesis. Other factors involved in initiation and promotion of pituitary tumors include loss of negative-feedback inhibition and estrogen-mediated or paracrine angiogenesis. Growth characteristics and neoplastic behavior may also be influenced by several activated oncogenes, including RAS and pituitary tumor transforming gene (PTTG).

Genetic Syndromes Associated with Pituitary Tumors

   Several familial syndromes are associated with pituitary tumors, and the genetic mechanisms for some of these have been unraveled. Multiple endocrine neoplasia (MEN) 1 is an autosomal dominant syndrome characterized primarily by a genetic predisposition to parathyroid, pancreatic islet, and pituitary adenomas. MEN 1 is caused by inactivating germline mutations in MENIN, a constitutively expressed tumor-suppressor gene located on chromosome 11q13. Loss of heterozygosity, or a somatic mutation of the remaining normal MENIN allele,leads to tumorigenesis. About half of affected patients develop prolactinomas; acromegaly and Cushing’s syndrome are less commonly encountered. Carney syndrome is characterized by spotty skin pigmentation, myxomas, and endocrine tumors including testicular, adrenal, and pituitary adenomas. Acromegaly occurs in about 20% of patients. A subset of patient have mutations in the R1α regulatory subunit of protein kinase A (PRKAR1A).

   McCune-Albright syndrome consists of polyostotic fibrous dysplasia, pigmented skin patches, and a variety of endocrine disorders, including GH-secreting pituitary tumors, adrenal adenomas, and autonomous ovarian function. Hormonal hypersecretion is the result of constitutive cyclic AMP production caused by inactivation of the GTPase activity of Gsα. The Gsα mutations occur postzygotically, leading to a mosaic pattern of mutant expression.

   Familial acromegaly is a rare disorder in which family members may manifest either acromegaly or gigantism. The disorder is associated with LOH at a chromosome 11q13 locus distinct from that of MENIN.

OTHER SELLAR MASSES

   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, providing 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 to evaluate cystic structure and tissue components of craniopharyngiomas. CT is useful to define calcifications and to 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 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 tumors 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 (<5mm) 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, internal 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 isointense with cerebrospinal fluid.

   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 diffi- cult 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., giomas may cause compressive symptoms. Histiocytosis X comprises 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 GnRH, GHRH, or CRH. In GnRH-producing tumors, children present with precocious puberty, psychomotor delay, and laughing-associated seizures. Medical treatment of GnRHproducing hamartomas with long-acting GnRH analogues effectively suppresses gonadotropin secretion and controls premature pubertal development. Rarely, hamartomas are also 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. These include dysgerminomas, which are frequently 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.

METABOLIC EFFECTS OF HYPOTHALAMIC LESIONS

   Lesions involving the anterior and preoptic hypothalamic regions cause paradoxical vasoconstriction, tachycardia, and hyperthermia. Acute hyperthermia is usually due to a hemorrhagic insult, but poikilothermia may also occur. Central disorders of thermoregulation result from posterior hypothalamic damage. The periodic hypothermia syndrome comprises episodic attacks of rectal temperatures. This region appears to contain an energy-satiety center where melanocortin receptors are influenced by leptin, insulin, POMC products, and gastrointestinal peptides. Polydipsia and hypodipsia are associated with damage to central osmoreceptors located in preoptic nuclei. 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.

EVALUATION

Local Mass Effects

   Clinical manifestations of sellar lesions vary, depending on the anatomic location of the mass and direction of its extension 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.

Feature of sellar mass lesions

Impacted Structure	Clinical Impact
Pituitary	Hypogonadism Hypothyroidism Growth failure and adult hyposomatotropism
Optic chiasm	Hypoadrenalism, 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 direct invasion of the optic nerves or obstruction of CSF flow leading to secondary visual disturbances also occurs. 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 hyperprolactinemia and 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. 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 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.

MRI

   Sagittal and coronal T1-weighted MRI imaging, before and after administration of gadolinium, allow 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. CT scan is indicated 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 with bony hyperostosis; craniopharyngiomas may be calcified and are usually hypodense, whereas gliomas are hyperdense on T2-weighted images.

Ophthalmologic Evaluation

   Because optic tracts may be contiguous to an expanding pituitary mass, reproducible visual field assessment that uses perimetry techniques should be performed on all patients with sellar mass lesions that abut the optic chiasm.Bitemporal hemianopia or superior bitemporal defects are classically observed, reflecting the location of these tracts within the inferior and posterior part of the chiasm. Homonymous cuts reflect postchiasmal and monocular field cuts prechiasmal lesions. Loss of red perception is an early sign of optic tract pressure. Early diagnosis reduces the risk of blindness, scotomas,or other visual disturbances.

Laboratory Investigation

   The presenting clinical features of functional pituitary adenomas (e.g., acromegaly, prolactinomas, or Cushing’s syndrome) should guide the laboratory studies 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 PRL; (2) insulinlike growth factor (IGF) I; (3) 24-h urinary free cortisol and/or overnight oral dexamethasone (1 mg) suppression test; (4) α subunit, FSH, and 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, 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.

SCREENING TESTS FOR FUNCTIONAL PITUITARY ADENOMAS

	Test	Comments
Acromegaly	Serum IGF-1 Oral glucose tolerance test with GH obtained at 0, 30 and 60 min	Interpret IGF-1 relative to age and gender matched controlled. Normal subject should suppress growth hormone to < 1 µg/L
Prolactinoma	Serum PRL	Exclude medications MRI of the sella should be ordered if prolactin is elevated
Chusing’s disease	24 urinary free cortisol Dexamethasone (1mg) at 11 PM, and fasting plasma cortisol measured at 8 AM ACTH assay	Ensure urine collection is total and accurate Normal subject suppress to <5 µg/L Distinguishes adrenal adenoma (ACTH suppressed) from ectopic ACTH or Cushing’s disease (ACTH normal or elevated)

Histologic Evaluation

   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 hypo- or hypersecretion syndromes caused directly by the adenoma or as a consequence of treatment. Thus, lifelong management and follow-up are necessary for these patients.

MRI technology 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 and can sometimes be restored by removing the tumor mass. Ideally, adenoma recurrence should be prevented.

TRANSSPHENOIDAL SURGERY Transsphenoidal 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, surrounding 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. 2-5). 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 improved visualization and access to tumor tissue.

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, internal hydrocephalus, and, occasionally, intrapituitary hemorrhage and apoplexy. Transsphenoidal surgery is sometimes used for pituitary tissue biopsy to establish a histologic diagnosis.

Whenever possible, the pituitary mass lesion should be selectively excised; normal tissue should be manipulated or resected only when critical for effective mass dissection. Nonselective hemihypophysectomy or total hypophysectomy may be indicated if no 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 hormonal replacement.

Preoperative mass effects, including visual field defects or compromised pituitary function, may be reversed by surgery, particularly when these deficits are not longstanding. 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 of the sella is rarely amenable to surgical cure; the surgeon must judge the risk-versus-benefit ratio of extensive tumor resection.

Side Effects Tumor size, the degree of invasiveness, and experience of the surgeon largely determine the incidence of surgical complications. The 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.

RADIATION Radiation 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 split 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 as yet unknown.

The role of radiation therapy in pituitary tumor management depends on multiple factors including the nature of the tumor, age of the patient, and 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 effective means for ablating significant postoperative residual nonfunctioning tumor tissue. In contrast, PRL-, GH-, and sometimes ACTH-secreting tumor tissues are amenable to medical therapy

Side Effects In 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, ACTH, 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 necessary 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 29 stereotactic radiotherapy may reduce damage to adjacent structures. Radiotherapy of pituitary tumors has been associated with an adverse mortality rate, 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.

MEDICAL Medical therapy for pituitary tumors is highly specific and depends on tumor type. For prolactinomas, dopamine agonists are the treatment of choice. For acromegaly and 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.