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Management of Lesions of the Pituitary Stalk and Hypothalamus

Lipscombe, Lorraine MD*; Asa, Sylvia L. MD, PHD†; Ezzat, Shereen MD‡

CME Review Article: Neuroendocrinology

The pituitary stalk and hypothalamus are susceptible to involvement by cystic, neoplastic, infectious, and inflammatory processes. The clinical features, diagnostic approach, and management of these lesions are reviewed. Patients may seek treatment for symptoms of anterior or posterior pituitary dysfunction, hyperprolactinemia, visual and neurologic symptoms because of mass effect, or hypothalamic impairment. The diagnostic evaluation includes assessment of pituitary and stalk function, magnetic resonance (MR) imaging, investigation for potential systemic disease, and, if necessary, pathologic examination. Imaging usually discloses a suprasellar or parasellar location, and certain specific etiologies may be suspected based on typical MR features. Although lesions involving the pituitary stalk and hypothalamus can present at any age, cystic lesions and most primary neuronal tumors are more typically seen in children, meningiomas and infectious and inflammatory processes are more common in young adults, and metastatic malignancy must be considered in older patients. In many cases management of stalk and hypothalamic masses is surgical. However, isolated, non-progressive lesions such as intrasellar Rathke’s cleft cysts or lymphocytic hypophysitis may be managed medically, and specific therapy for lesions associated with systemic diseases may be indicated before surgical consideration.

Learning Objectives:

* Contrast various treatment options for craniopharyngioma and other cystic lesions of the pituitary stalk and hypothalamus.

* Summarize the best surgical or alternative approaches to treating primary tumors in this region.

* Identify alternatives to surgery for treating inflammatory disorders of this region.

* Distinguish the advantages of medical and surgical treatment measures when systemic disorders involve the pituitary stalk or hypothalamus.

*Fellow, Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

†Professor and Pathologist-in-Chief, Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada.

‡Professor and Director, Endocrine Oncology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

Chief Editor’s Note:

This article is the 3rd of 36 that will be published in 2003 for which a total of up to 36 Category 1 CME credits can be earned. Instructions for how credits can be earned appear following the Table of Contents.

Address correspondence and reprint requests to: Shereen Ezzat, M.D., 600 University Avenue, Suite 437, Mount Sinai Hospital, Toronto, Ontario M5G 1X5 Canada. Telephone: 416–586-8505; Fax: 416–586-8834; E-mail: sezzat@mtsinai.on.ca

The authors have disclosed that they have no significant relationship with or financial interest in any commercial company pertaining to this educational activity.

Mass lesions involving the hypothalamic-pituitary system are becoming an increasingly common diagnostic challenge for endocrinologists, particularly since the introduction of magnetic resonance (MR) imaging. This article will focus on those lesions that involve primarily the hypothalamus and pituitary stalk, highlighting the clinical, biochemical, and radiographic features that distinguish them from the more common primary pituitary adenomas. For each type of lesion, a management approach based on published findings and the authors’ experience will be presented.

The anatomy and blood supply of the hypothalamus and pituitary gland renders it susceptible to involvement by central nervous system (CNS) lesions, and from a number of systemic disorders. These lesions generally include primary CNS tumors, cysts, metastases, and infiltration by inflammatory or infectious processes (Table 1). Patients may seek treatment for symptoms and signs caused by local mass effect, hormonal alterations, or with an asymptomatic abnormality on brain imaging.

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SIGNS AND SYMPTOMS OF HYPOTHALAMIC AND PITUITARY STALK LESIONS

The clinical features of lesions involving the hypothalamus and pituitary stalk depend on their location, their degree of adjacent extension, and their rate of progression. For example, slow-growing masses tend to cause less tissue destruction and symptoms caused by compensatory processes. The hypothalamus is situated below the third ventricle and above the optic chiasm and sella turcica, which contains the pituitary gland. The connecting pituitary stalk passes inferiorly through an opening in the dura, allowing delivery of hypothalamic peptides to the pituitary gland. Peptides mediating release of anterior pituitary hormones are produced in the anterior hypothalamus; ADH and oxytocin, which are stored and released by the posterior pituitary, are produced in the paraventricular and supraoptic nuclei of the hypothalamus respectively.

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Anterior Pituitary Hormone Dysfunction

Lesions involving the hypothalamus and stalk may seek treatment for evidence of anterior pituitary hormone deficiency, either caused by compromise of hypothalamic releasing peptides or caused by compression of the pituitary gland. Patients may seek treatment for evidence of gonadal dysfunction, secondary hypothyroidism, and even cortisol deficiency. Growth failure and lack of secondary sexual development may be seen in children. With interruption of hypothalamic peptide delivery, low basal hormone levels may be seen but administration of stimulating hormones may result in a sluggish response. In addition, germ cell tumors and rare gangliocytomas may seek treatment for syndromes of hormonal excess such as precocious puberty.

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Posterior Pituitary or Stalk Dysfunction

Lesions that compress or infiltrate the pituitary stalk often result in hyperprolactinemia, because of interruption of the dopaminergic inhibition of anterior pituitary prolactin secretion. Serum prolactin (PRL) elevations are typically between 20 to 100 ng/mL; a PRL level greater than 200 ng/mL is more consistent with a PRL-producing pituitary adenoma.

Clinical diabetes insipidus is far more common with nonpituitary sellar or parasellar masses than with pituitary adenomas. Impaired antidiuretic hormone (ADH) secretion and diabetes insipidus may result from infiltration or compression of the posterior pituitary gland, the pituitary stalk, the hypothalamus, or the paraventricular region of the third ventricle. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) may also occur with these lesions.

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Visual and Neurologic Symptoms

Visual complaints are common with sellar or parasellar masses because of the proximity of the sella turcica to the optic chiasm, nerves, and tracts. Lesions anterior to the optic chiasm can produce unilateral visual loss, whereas lesions that are more posterior along the optic tract may cause homonymous hemianopsias. Bitemporal visual field deficits may result from masses originating from within the sella, because of superior chiasmal compression. Lesions involving the chiasm, such as optic gliomas, may produce more unusual visual deficits. Lesions involving the cavernous sinus may also result in typical cranial neuropathies.

Headache is often a prominent symptom at presentation of sellar or parasellar lesions. Distortions of the diaphragma sella, irritation of the parasellar dura or, in more severe cases, meningitis or raised intracranial pressure are likely causes of headache in these patients.

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Hypothalamic Dysfunction

In addition to hormonal abnormalities, hypothalamic lesions may lead to disruption of appetite control causing polyphagia or starvation, and impairment of temperature regulation and autonomic activity.

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SPECIFIC LESIONS

Lesions involving the hypothalamus and pituitary stalk include predominantly cystic lesions (Table 2), primary tumors (Table 3), and either infectious or autoimmune inflammatory processes (Table 4). In addition to inflammatory illnesses, systemic diseases such as metastatic or hematologic malignancies and brown tumors in patients with chronic renal failure may also infiltrate the hypothalamic-pituitary system (Table 4). A brief overview of the clinical features of and management approach to the more common lesions is outlined below.

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Cystic Lesions

Craniopharyngiomas.

Craniopharyngiomas are thought to arise from remnants of Rathke’s pouch [1]. They represent 2–4% of intracranial neoplasms and, as the most frequent sellar tumor of childhood, they comprise 10% of CNS tumors in children [2]. They can occur at any age from infancy [3] to old age [4], with the peak between 5–20 years of age, and a second small peak in the sixth decade. Craniopharyngiomas are most likely to produce symptoms because of their aggressive nature. Approximately 75% of patients complain of symptoms of mass effect, such as headache and visual field disturbances [5]. Pituitary hormone deficiency may also occur. In children, growth hormone deficiency can present in up to 93% of cases [6]. Sexual dysfunction caused by gonadotropin deficiency is the most common endocrine complaint in adults. With stalk interruption hyperprolactinemia can occur, and diabetes insipidus is found in approx-imately 25% of patients [6,7].

Craniopharyngiomas most commonly are calcified, cystic suprasellar masses; only 15% of cases have a predominantly intrasellar component [5]. Tumoral calcification is best appreciated on computed tomography (CT) scan, and is seen in 70–90% of these lesions in children and 40–60% in adulthood [8]. On MRI, these lesions usually display mixed solid and cystic components (Fig. 1) [2]. The cystic portions demonstrate a high signal on T1-weighted images before contrast administration [9,10 because of their lipid content.

Although craniopharyngiomas may be as small as 1 cm in size, the majority are larger at the time of diagnosis. The epithelium is characterized by a superficial keratinizing layer. The lesions usually contain a thick oil-like fluid, which is described as “black sludge” or “machinery oil”. Cholesterol crystals and calcification may be seen on gross examination, and rarely they may contain calcified tissues such as bone or teeth.

If left alone, craniopharyngiomas are extremely infiltrative. They can cause extensive tissue damage, extending into the hypothalamus with obstruction of the third ventricle and hydrocephalus. Uncommonly, craniopharyngiomas may spontaneously rupture or form abscesses.

Because of their highly infiltrative nature, they are often incompletely excised surgically. There is a 10–40% recurrence rate, particularly in younger patients. For this reason, a subfrontal surgical approach may be required to ensure adequate exposure. Transsphenoidal surgery is suitable only for those minority of cases with mainly intrasellar tumor, or for palliative subtotal removal or drainage for patients who have had failed previous surgery [11]. Postoperative radiation is desirable to reduce disease recurrence [6,11]. No medical therapy is currently known for these tumors, but patients often require hormone replacement for anterior pituitary insufficiency and diabetes insipidus.

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Rathke Cleft Cysts.

Rathke cleft cysts are more frequently seen in adulthood presenting at a mean age of 38 years [7]. They are typically intrasellar and asymptomatic, but suprasellar extension can be seen in up to one third of cases. As with craniopharyngiomas, they can present with compressive symptoms or varying degrees of pituitary dysfunction. However, because of their more cystic nature, compressive features are not as pronounced as with comparably sized craniopharyngiomas.

CT scans reveal low density cystic areas with capsular enhancement in most cases; the MRI appearance is variable [12–14]. Unfortunately, there are no specific radiologic features distinguishing Rathke’s cleft cysts from other purely cystic lesions.

Diagnosis is confirmed by morphologic examination, which reveals a cyst lining characterized by ciliated cuboidal or columnar epithelium resembling respiratory epithelium. Goblet cells and squamous elements are occasionally seen.

The management of Rathke’s cleft cysts involves either observation or surgical drainage with or without partial excision [15]. The recurrence rates for these cysts are relatively low [12]. Most symptoms and signs are relieved postoperatively, but permanent hypopituitarism and diabetes insipidus are not unusual.

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Epidermoid, Dermoid, and Arachnoid Cysts.

Dermoid and epidermoid cysts are epithelial-lined intracranial cysts seen most often in childhood. They are found most commonly at the cerebellopontine angle and in the suprasellar region. In contrast, CSF-containing arachnoid cysts may be congenital or acquired, and may be intrasellar or suprasellar. As with craniopharyngiomas, these lesions may produce varying degrees of hypopituitarism, stalk compression, visual field defects, and nonspecific neurologic symptoms [16,17]. Arachnoid cysts are least likely to cause pituitary compression and symptoms.

Imaging usually discloses the largely cystic nature of these lesions, but their features are nonspecific. As with Rathke’s cleft cysts, diagnosis is made on pathologic examination. Epidermoid cysts are lined by keratinizing squamous epithelium, whereas dermoid cysts are distinguished by the additional presence of skin appendages such as hair follicles and sweat glands. Arachnoid cysts contain clear and colorless fluid, and are lined by arachnoid laminar connective tissue with a single layer of flattened epithelium.

In most cases, symptomatic lesions are managed by surgical drainage or excision. The prognosis is generally good, with low recurrence rates. Rarely, epidermoid and dermoid cysts can rupture resulting in chemical meningitis caused by keratin debris [18], or degenerate into squamous carcinoma [19]. In the absence of compressive features or pituitary function compromise, a conservative medical approach with surveillance and annual imaging can be justified.

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Primary Tumors

Gangliocytomas.

These hypothalamic neuronal tumors are very rare neoplasms that have been reported in the literature under the name of “gangliocytomas” or “ganglioneuromas” [20]. Other names include hamartomas and “choristoma” [21,22]. They are composed of mature neurons resembling hypothalamic ganglion cells and are thus capable of producing hypothalamic peptides.

The presentation of gangliocytomas can be attributed to compression or destruction of hypothalamic tissue, the pituitary gland, stalk, or suprasellar structures. When these tumors are hormonally active, they can cause pituitarymediated endocrinopathies such as acromegaly, precocious puberty, Cushing’s disease, and amenorrhea-galactorrhea.

The most common location of gangliocytomas is in the hypothalamus or tuber cinereum, with different grades of involvement of the third ventricle. If they are outside the hypothalamus, they are frequently attached to the hypothalamus by a thin connection. These tumors can also be found within the pituitary gland, and like pituitary adenomas, they are nonenhancing on MRI. Caused by their nonspecific features, diagnosis is usually made at the time of surgery. Histologic examination typically reveals hypothalamic ganglion cells in neurons. Some may be associated with pituitary adenomas, most often in patients with acromegaly where the neurons contain GHRH and the pituitary harbors a sparsely-granulated GH adenoma.

Surgical resection is the treatment of choice and can be curative. When surgery cannot accomplish this result, the prognosis has varied. Some of these tumors, particularly those associated with precocious puberty, may follow a benign course with little growth.

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Gliomas.

Gliomas can rarely selectively involve the hypothalamus and/or the pituitary gland [23,24]. They can mimic pituitary adenomas clinically and radiographically, presenting as sellar mass lesions. Typically, these lesions present after sellar or suprasellar radiation, and tend to be aggressive [25–36].

Gliomas of the optic nerve, however, usually occur in children or adolescents [37–39], or in those with predisposing syndromes such as neurofibromatosis or Beckwith-Wiedemann syndrome [40,41]. Patients typically present with visual loss, but occasionally endocrinopathies such as hypopituitarism, diabetes insipidus and even precocious puberty can be seen [38,39].

Unfortunately, there are no distinguishing features on sellar imaging by MRI or CT. As with many sellar lesions, histologic examination reveals the diagnosis.

Gliomas in children tend to be low-grade and thus have a relatively good prognosis. Chiasmal lesions, however, can be more aggressive [37]. When optic gliomas occur sporadically in adults, they are usually rapidly fatal tumors [42,43].

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Meningiomas.

Meningiomas are tumors of arachnoid and meningothelial cells which can occur in the sellar and parasellar areas in approximately 20% of cases [44]. The peak age at diagnosis is between 40 and 50 years, and they are more common in women [45] possibly related to their expression of progesterone and estrogen receptors [46]. Common sites of presentation include the sphenoid ridge, tuberculum sellae and, rarely, the clivus. They are usually seen in the suprasellar region, and completely intrasellar tumors are rare [47]. They can also arise after cranial irradiation [30,36,48–50]. Patients can present with compressive symptoms including stalk interruption and/or hypopituitarism. Meningiomas are typically isointense on T1-weighted and T2-weighted MRI, frequently have prominent vascularity, and are seen as distinct from the pituitary gland in most cases. These and other radiographic characteristics can often distinguish these lesions from pituitary adenomas and other sellar masses.

Meningiomas are generally managed by surgical resection [51]. Because of their high vascularity and propensity for intraoperative bleeding, a craniotomy is usually preferred underscoring the importance of pre-operative diagnosis. The recurrence rate for these tumours is low, and the prognosis largely depends on the degree of resection and preservation of surrounding structures.

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Germ Cell Tumors.

Germ cell tumors are derived from residual germ cells along the midline; they are generally identical to germ cell tumors of the gonads and mediastinum. Intracranial germ cell tumors represent less than 1% of all intracranial neoplasms, but in children they constitute up to 6.5% of such lesions [52]. These tumors include germinomas, embryonal cell carcinomas, and teratomas. After the pineal gland, the suprasellar region represents the second most common site of involvement. They are more common in patients under the age of 20 years, and they occur more often in males than in females.

These lesions can be associated with hypopituitarism and visual disturbances, and diabetes insipidus occurs in up to 80% of patients. Larger lesions can cause intracranial hypertension and hydrocephalus, psychosis and dementia [52–57]. Furthermore, some tumors can present with precocious puberty, either caused by hypothalamic destruction and loss of gonadal inhibition, or caused by the production of β-chorionic gonadotropin (β-hCG) by the neoplastic germ cells. Elevated circulating levels of alpha-fetoprotein (AFP) can also be seen, indicating the presence of yolk sac elements that characterize embryonal carcinoma.

The most common germ cell tumor, the germinoma, is usually a well-demarcated tumor that has high density on CT scan and enhances with contrast [57]. Teratomas can exhibit fat densities and calcifications that are recognized radiologically. MRI is more sensitive than CT scan for these features.

The diagnosis of germ cell tumors is usually confirmed on pathologic examination. For those in whom β-hCG and AFP positivity are found preoperatively or on immunohistochemical staining, measurement of these markers in blood is useful to detect recurrence.

Surgery for germ cell tumors is rarely curative [58]. If the diagnosis is suspected preoperatively, biopsy can be performed to type the lesion and determine whether surgery or other modalities such as radiation or chemotherapy are indicated. Germinomas are uniquely radiosensitive and long-term remission is achieved in approximately 70% of patients [54]. However, the presence of more aggressive elements in mixed tumors can predict failure of radiotherapy. Other tumors are more aggressive, and despite maximal treatment they may recur or metastasize both within and beyond the central nervous system [59].

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Chordomas.

Chordomas are rare midline lesions that are thought to derive from remnants of the notochord [60]. They occur most often in the sacral region, but they may also present in the region of the clivus, the sphenoid, or within the sella turcica [61]. These are generally slow growing tumors most often seen in children and young adults. They tend to be more locally aggressive in patients over the age of 30 years. Parasellar involvement may occasionally manifest as anterior pituitary insufficiency, but typically chordomas of the clivus present with pain, oculomotor palsies, cerebellopontine angle syndrome and intracranial hypertension.

Chordomas are distinguished by their lobulated, calcified, and expansile osteolytic nature. They characteristically elevate the periosteum, in which case they may be suspected on the basis of the radiologic findings [62]. Surgery is the preferred initial therapeutic approach, and radiotherapy is indicated for incompletely resected lesions. Mean survival is about 4–5 years, and metastases to lung, liver, bone and lymph nodes can rarely occur.

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Inflammatory Lesions

Lymphocytic Hypophysitis.

Although considered rare at the time of its first description of the entity in 1962 [63], this condition is becoming increasingly recognized. The disease shows a striking female predilection of approximately 8.5:1, and affects young women during late pregnancy or in the postpartum period in 70% of cases [64]. The mean age of presentation is 34.5 years in females and in 44.7 years in males [64]. It is associated with other autoimmune disorders in nearly 25% of cases. Primary thyroiditis is the most frequent associated condition, and it has also been described in association with adrenalitis, atrophic gastritis, and parathyroiditis [64–66]. Its association with pregnancy has been attributed to hyperplasia of lactotrophs, that may trigger an immune response. Although the exact pathogenesis of this entity is unknown, it is widely suspected to be an autoimmune phenomenon (62). The fact that nearly one quarter of patients have another autoimmune condition supports this contention. Anti-pituitary antibodies have been detected in a small number of patients and can be used in support of the diagnosis [67,68]. Most cases involve the anterior lobe and are assumed to be attributable to antibodies against adenohypophysial cells. In some patients, the clinical presentation and biochemical findings implicate a single hormone secreting cell type as the target [69–71]. Rarely, patients can present with diabetes insipidus alone caused by inflammation restricted to the posterior lobe and stalk; this disorder has been named infundibular neurohypophysitis [72–74].

Clinically, lymphocytic hypophysitis may have an acute or insidious onset and its course may range from severe and even lethal to a mild and transient dysfunction. The most common manifestations are partial or total hypopituitarism in 63% to 68% of patients, mass effects in 56% to 70%, hyperprolactinemia with or without suprasellar extension in 20% to 38%, and diabetes insipidus in 19% of cases [64].

In addition to its association with pregnancy, another distinguishing feature of this condition is the selective loss of pituitary cell function as mentioned above [75]. Even though isolated corticotropin deficiency is rare, it represents the most common isolated type of anterior pituitary hormone deficiency encountered in patients with proven or putative lymphocytic hypophysitis [76–82]. Isolated TSH deficiency [80], selective absence of gonadotropins [65], and isolated diabetes insipidus [18,26,27,65] are also reported.

CT or MR-imaging can reveal features of an enlarging pituitary mass in up to 95% of patients, with frequent evidence of suprasellar extension (Fig. 2). The radiographic appearance cannot be easily distinguished from a pituitary adenoma, however some specific features on MRI exist. These include loss of the hyperintense “bright spot” signal of the normal neurohypophysis, thickening of the pituitary stalk, and enlargement of the neurohypophysis if it is clinically involved [72]. These radiographic criteria need prospective evaluation.

Because of the lack of any specific and reliable clinical, biochemical or radiographic markers for this condition, a preoperative diagnosis of lymphocytic hypophysitis is rarely suspected [64,83–86]. Most cases are diagnosed postoperatively, and lesions are characterized by diffuse infiltration of lymphocytes with variable degrees of reactive fibrosis.

Patients who present with hyperprolactinemia and a sellar mass are often presumed to have a prolactinoma, and a trial of dopamine-agonist therapy is thus attempted. On prospective evaluation of such cases treatment has been shown to improve visual fields and reduce prolactin levels, however it has not altered the size of pituitary masses [85,87–91]. Thus, an inadequate response with an attempt at therapeutic control of a presumed prolactinoma can serve as a diagnostic clue in patients with lymphocytic hypophysitis.

The natural history of lymphocytic hypophysitis is variable. In more severe cases, progressive and irreversible hypopituitarism may occur, and may be fatal in up to 19% of cases because of unrecognized adrenal failure. Although spontaneous partial or complete recovery has been described [84,92–97], most patients experience sustained losses requiring long-term replacement.

Treatment with a dopamine agonist can be attempted for improvement of visual fields and hyperprolactinemia, but it does not affect sellar enlargement. Corticosteroid therapy is advocated to reduce inflammation, and has been effective in some patients [88,98–100]. The efficacy of corticosteroids in this disorder, however, remains largely unproven with no established benefit [83,86]. Surgery should be performed in patients with progressive compressive features, or in those with deterioration despite medical treatment [86,101].

Transsphenoidal surgery can be both diagnostic and therapeutic; it has resulted in amelioration of mass symptoms [83,85,86,94,98,99,101–107], hyperprolactinemia [88,105,108–111] and pituitary function [94,98,104] in some patients. However, surgical intervention can also be associated with further deterioration of visual field defects [112, the development of diabetes insipidus, and even new or worsening hypopituitarism [83,90,100,105,112,113]. These findings highlight the importance of proper diagnosis and conservative management of patients with lymphocytic hypophysitis. We propose that in cases of suspected hypophysitis, a frozen section should be performed to confirm the diagnosis and avoid aggressive resection of viable pituitary tissue.

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Granulomatous Hypophysitis.

“Giant cell granuloma” or granulomatous hypophysitis is a rare condition that is characterized by isolated localized granulomatous inflammation of the pituitary gland [114–118]. In contrast to lymphocytic hypophysitis, there is no gender predilection. The mean age at diagnosis is 21.5 years in females and 50 years in males, and most cases are diagnosed at autopsy (65). The etiology is unknown. It has been suggested that it represents an autoimmune phenomenon related to lymphocytic hypophysitis [118,119], but there is no evidence to support this postulate.

Patients can present with meningitis, hyperprolactinemia, and diabetes insipidus. They can also present with sellar enlargement and hypopituitarism, mimicking a clinically nonfunctional pituitary adenoma.

Radiologic imaging typically demonstrates a nonspecific sellar mass, with or without suprasellar extension. In every case, the possibility of underlying infection or sarcoidosis must be excluded.

A closely related condition is referred to as Xanthomatous hypophysitis, the least well-known member of the primary hypophysitis family [120]. It is defined histologically by the presence of numerous foamy histiocytes with variable numbers of lymphocytes. This localized and lipid-rich inflammatory process resembles xanthomatous inflammatory processes in other tissues, such as xantomatous cholecystitis, endometritis or pyelonephritis, in which the inflammation is thought to be incited by cell debris of endogenous or infectious origin. Unlike the other forms of hypophysitis, these lesions are generally cystic in quality, either on radiologic or surgical evaluation, and it could be argued that the inflammation is a response to the components of a ruptured cyst. These is no gender predilection and, similarly, no infectious process has been implicated in the pathogenesis of xanthomatous hypophysitis.

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Lesions Associated With Systemic Diseases

Sarcoidosis.

Involvement of the central nervous system, or neurosarcoidosis can be seen in 5% to 15% of patients with sarcoidosis, and when it occurs it seems to have a predilection for the hypothalamic-pituitary region [121]. Neurosarcoidosis is usually associated with systemic disease; only 5% of cases are limited to the central nervous system [121]. Sarcoidosis tends to infiltrate the hypothalamus and pituitary stalk most often, but the pituitary gland can also be involved causing varying degrees of hypopituitarism [122]. Diabetes insipidus is common with pituitary stalk infiltration, and hyperprolactinemia can occur. Cranial neuropathies are also common with CNS involvement. Although unusual, cases of sarcoidosis isolated to the hypothalamic-pituitary system are reported [122] rendering the distinction from other granulomatous disease difficult.

Sarcoid lesions appear isointense on T1-weighted images and variable on T2-weighted MRI images. With contrast, these lesions typically enhance and are frequently accompanied by periventricular and leptomeningeal enhancement [123]. Sarcoidosis can resemble a sellar mass and mimic a pituitary adenoma [124] and, in rare instances, these masses may be cystic.

Sarcoidosis should be considered in the differential diagnosis of sellar masses, even in the absence of systemic disease. Because intrathoracic lesions occur in about 70% of cases [122], the presence of hilar adenopathy on chest x-ray or CT scan should be sought out. An elevated erythrocyte sedimentation rate and serum calcium can be helpful if present but are less commonly seen in isolated disease [125]. Serum angiotensin converting enzyme (ACE) levels are sometimes used in the diagnostic work-up of sarcoidosis, however the low sensitivity and specificity (60% and 25% respectively) associated with this test limits its utility [126]. Elevated ACE levels that decrease with immunosuppressive therapy are reported in isolated neurosarcoidosis [122].

CNS involvement is one of the indications for corticosteroid treatment in sarcoidosis. A trial of steroids is warranted in suspected cases of sellar or parasellar disease. Response to treatment is variable, and cyclophosphamide should be considered for resistant cases.

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Tuberculoma.

Despite the availability of effective chemotherapy, up to 4% of space-occupying lesions in the sellar or parasellar region are still caused by tuberculomas, with most occurring in developing countries [127]. Tuberculomas involving the hypothalamus or pituitary rarely present clinically, and are more often seen at the time of autopsy.

In one of the largest case series thus far, 18 cases of intrasellar tuberculomas from India were described [127]. The age of the patients ranged from 8 to 43 years old, 72% were female, and only 6 patients (33%) had a history of systemic tuberculosis. All patients presented with headache, 65% had visual field disturbances, and 39% of patients had pituitary endocrine dysfunction and/or hypopituitarism.

Imaging reveals a sellar mass in all cases, with 60% suprasellar and 33% sphenoid sinus extension [125]. Of those who underwent MRI, 50% had pituitary stalk thickening. A thickened stalk has been reported in up to 86% of cases, and leptomeningeal enhancement can be seen with associated meningitis (Fig. 3) [128].

Granulomatous inflammation was seen in all cases, with half of them being non-necrotizing [127]. The remaining cases were characterized by caseating necrosis surrounded by epithelioid macrophages, lymphocytes, plasma cells, and giant cells. Interestingly, acid fast bacilli are not usually seen in the specimen.

Treatment generally consists of antituberculous antibiotics with possible surgical decompression via the transphenoidal approach to avoid CSF contamination [127]. Although uncommon, tuberculoma should be included in the differential diagnosis of hypothalamic and pituitary lesions, particularly in those from endemic areas.

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Langerhans Cell Histiocytosis.

Formerly known as Histiocytosis-X, Langerhans cell histiocytosis or granulomatosis, is a localized, multifocal or disseminated proliferation of epithelioid histiocyte-like dendritic Langerhans cells. It is currently thought to be a reactive rather than neoplastic process with an immunologic etiology affecting young adults [129]. It typically involves the lungs, bones, and hypothalamic-pituitary system causing diabetes insipidus and, rarely, hypopituitarism. In addition, isolated lesions involving the hypothalamus and pituitary are reported [130–133].

Radiologic appearance is not diagnostic [134] and the nature of the disorder, when localized, is usually established after surgery. Lytic lesions of the skull should be sought as a diagnostic clue, and a chest X-ray should be performed to assess for the presence of interstitial lung disease.

Prognosis is variable; when systemic involvement is manifest, it is frequently fatal. Isolated lesions can progress rapidly to widely disseminated disease that is unresponsive to any form of therapeutic intervention. Surgery has been reported to be curative for localized lesions [133, and radiotherapy has been used postoperatively with success in cases with isolated involvement of this region [135.

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Lymphoma/Leukemia.

When lymphoma or leukemia involve the central nervous system, there may be subcapsular infiltration of the hypothalamus or pituitary gland [136]. Diabetes insipidus is the most common clinical presentation, but patients can occasionally present with SIADH [136,137]. Primary lymphoma involving the hypothalamus can also result in hypopituitarism [138] or chiasmal compression [139]. Rarely, sellar involvement with lymphomas, leukemias or plasmacytomas can present as sellar masses [140–144].

The radiographic appearance of these lesions is not characteristic, and the diagnosis usually requires microscopic evaluation. In most patients there is evidence of systemic disease, and only rarely can the lesion truly be considered solitary [145,146].

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Metastatic Lesions.

Because the pituitary gland is highly vascular, blood-borne metastases from distant malignancies to the pituitary are relatively common [147,148]. Involvement of the posterior lobe is more frequent than the anterior lobe [147], and the most common tumors of the neurohypophysis are metastases [149].

The most common primary site of these lesions in the lung, breast and gastrointestinal tract [150–154]. Among patients with breast carcinoma, pituitary metastases are statistically correlated with spread to other endocrine organs [151], suggesting a common mechanism that may implicate hormonal factors.

Most pituitary metastases are clinically asymptomatic and discovered incidentally at autopsy. Occasionally, however, patients may seek treatment for a sellar tumor and no prior history of malignancy [150]. New onset diabetes insipidus at an advanced age should raise suspicion for posterior lobe or pituitary stalk metastases [149]. Large tumors can invade the cavernous sinus and its associated structures causing headache, visual field defects, ophthalmoplegia and ptosis [152]. Anterior pituitary involvement with hypopituitarism is rare [150]. Radiologically, stalk thickening may be seen. These lesions can be indistinguishable from pituitary adenoma.

The correct diagnosis of these tumors is based on histologic, immunohistochemical and ultrastructural features. In patients with an unknown primary malignancy, the major differential diagnosis involves the distinction of these lesions from pituitary adenoma. Mitotic activity, cellular and nuclear pleomorphism are the hallmarks of malignancies, but these features can also be present in pituitary adenomas. In general, pituitary adenomas are readily characterized by their immunohistochemical profile, but tumors that are immunonegative for the usual hormones should be evaluated carefully in situations where the possibility of metastasis is raised.

Because these patients have disseminated malignancy, the therapy is aimed at palliation. Surgical decompression with or without radiotherapy can relieve symptoms but does not alter outcome [150].

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CONCLUSIONS

Lesions involving the hypothalamus and/or pituitary stalk can present in a number of ways, ranging from anterior or posterior pituitary dysfunction, hyperprolactinemia, or visual and neurologic deficits. In most cases, the presenting signs and symptoms merely aid in localizing the lesion and other features must be considered for a more specific diagnosis (Fig. 4). Radiographic studies can characterize certain lesions, and a mainly suprasellar or parasellar location can help to differentiate them from pituitary adenomas.

The age of the patient is also important. In general, cystic masses and primary neuronal tumors are more frequently seen in children, although Rathke’s cleft cysts and meningiomas do occur more often in adults. Metastatic disease should be strongly suspected in older patients presenting with disease involving the hypothalamus or stalk. Inflammatory lesions such as lymphocytic or granulomatous hypophysitis can occur at any age, although most of these diseases appear to be more common in young and middle-aged individuals. If an inflammatory condition is suspected, associated systemic manifestations should be sought.

Clearly, a treatment approach based on surgically excised morphologically examined tissue would be ideal. We propose, however, that in many cases of non-invasive lesions of the hypothalamic/pituitary stalk surgical intervention may not be essential. Isolated, non-progressive lesions such as suspected intrasellar Rathke’s cleft cysts or lymphocytic hypophysitis can be managed medically with appropriate pituitary hormone replacement and periodic imaging. In cases of lesions associated with systemic diseases, specific antibiotic, chemotherapeutic, and/or immunosuppressive therapy before surgical intervention is justifiable. Surgical decompression and tissue diagnosis should be reserved for resistant or progressive disease.

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