Clinically Nonfunctioning Sellar Masses
Many types of lesions present as a mass within or near the sella turcica (Table 9-1). The majority of sellar masses are pituitary adenomas, even those that are not obviously associated with clinical syndromes. The majority of these clinically nonfunctioning pituitary adenomas are gonadotroph adenomas, but some are relatively silent lactotroph, somatotroph, corticotroph, and thyrotroph adenomas. Determining whether a sellar mass is a pituitary adenoma or other type of sellar mass is important; and if it is a pituitary adenoma, the type of adenoma is significant, because that distinction will determine optimal treatment.
Table 9-1
Cysts (Rathke’s cleft, arachnoid, dermoid, epidermoid)
Infiltrative and granulomatous diseases (sarcoidosis, Langerhans cell histiocytosis, tuberculoma)
Natural History of a Pituitary or Parasellar Mass
Prior to the advent of sensitive pituitary imaging techniques, a wide spectrum of clinical sequelae were evident from the effects of an enlarging mass arising from within the pituitary or its adjacent structures (Table 9-2). Although it is today relatively uncommon for such a mass to be invasive at the time of diagnosis, the relative subtlety of clinical features may delay the anatomic imaging of such a mass.
Table 9-2
Local Neurologic Effects of a Pituitary or Hypothalamic Mass
| Impacted Structure | Clinical Effect |
| Optic tract | Loss of red perception, bitemporal hemianopsia, superior or bitemporal field defect, scotoma, blindness |
| Hypothalamus | Temperature dysregulation, appetite disorders, obesity, thirst disorders, diabetes insipidus, sleep disorders, behavioral dysfunction, autonomic nervous system dysfunction |
| Cavernous sinus | Ptosis, diplopia, ophthalmoplegia, facial numbness |
| Temporal lobe | Uncinate seizures |
| Frontal lobe | Personality disorder, anosmia |
| Central | Headache, hydrocephalus, psychosis, dementia, laughing seizures |
Types of Sellar Masses
Any pituitary adenoma type may first be recognized as a sellar mass, even those that usually cause recognizable clinical syndromes, such as corticotroph, somatotroph, and lactotroph adenomas. In some situations, the clinical syndrome (e.g., Cushing’s syndrome or acromegaly) is present but not recognized; in other situations, the clinical syndrome is relatively subtle or nonexistent. The latter have been referred to as “silent” adenomas.1–3 It is probably more accurate, however, to regard the clinical presentations of these adenomas as a spectrum from clinically obvious (e.g., frank acromegaly), to clinically subtle (e.g., slight increase in ring size but still overall normal appearance), to clinically silent (e.g., no clinical manifestations but a high IGF-1),4,5 to silent (e.g., normal IGF-1 but immunostaining of excised tissue for growth hormone) (Table 9-3).
Table 9-3
Spectrum of Functionality of Pituitary Adenomas
| Term | Description |
| Clinically obvious | Typical physical features of excessive hormonal hypersecretion |
| Clinically subtle | Subtle physical features of excessive hormonal hypersecretion |
| Clinically silent | Elevated serum concentration of pituitary hormone but not even subtle clinical manifestations |
| Silent | Type of adenoma identifiable only by immunostaining; normal serum concentration of hormone normally secreted by that cell type |
Pituitary Hyperplasia
Hyperplasia of anterior pituitary cells can result from several causes and results in generalized enlargement of the pituitary. During pregnancy, lactotroph hyperplasia occurs as the result of estrogen stimulation. When a target gland fails, the resulting lack of feedback inhibition on the corresponding pituitary trophic hormone-secreting cells results in hyperplasia. For example, thyrotroph hyperplasia occurs as a consequence of longstanding and untreated primary hypothyroidism, and gonadotroph hyperplasia occurs as a consequence of longstanding and untreated primary hypogonadism.6–9 When a neuroendocrine tumor secretes growth hormone–releasing hormone excessively, the result is somatotroph hyperplasia.10
Lymphocytic Hypophysitis
Lymphocytic infiltration of the pituitary usually occurs in late pregnancy or postpartum but can also be seen in women who are not pregnant and infrequently in men.11 It is characterized by headaches whose intensity is out of proportion to the size of the lesion and by hypopituitarism, in which adrenal insufficiency is unusually prominent.
Benign Tumors, Nonpituitary
Rathke’s Cleft and Other Cysts
During early embryogenesis, the anterior and intermediate lobes of the pituitary gland arise from Rathke’s pouch. If the pouch fails to obliterate, cystic remnants remain at the interface between the anterior and posterior pituitary lobes. These small cysts (<5 mm) are found in about 20% of pituitary glands at autopsy.12 Occasionally a pituitary adenoma may also contain small cleft cysts.13 The imaging of these cysts on MRI reveals hyperdense or hypodense masses on either TI or T2 images. CT scan reveals the presence of homogenous hypodense areas that may allow differentiation from pituitary adenomas.14 Other sellar cysts include arachnoid, epidermoid, and dermoid cysts. Although these lesions develop mainly in the cerebellopontine angle, they may also occur in the suprasellar region. Clinical features of compression include internal hydrocephalus, visual disturbances, and rarely growth hormone or ACTH deficiency, hyperprolactinemia, and diabetes insipidus.15–17 Rarely, a squamous cell carcinoma may develop in the cyst.18
Craniopharyngiomas
Craniopharyngiomas19 are solid or mixed solid-cystic tumors that arise from remnants of Rathke’s pouch, either intrasellar or suprasellar. About half present clinically during childhood and adolescence, but some do not present until age 70 or 80 years. The major presenting symptoms are growth retardation in children and abnormal vision in adults. Anterior pituitary hormonal deficiencies and diabetes insipidus are also common. MRI often reveals a heterogeneous signal, and CT scan often shows calcifications. When cut, they often ooze a viscous fluid described as looking like “crankcase oil.” Histologically, they show their epithelial origin, either an adamantinomatous or papillary pattern.
The endocrine manifestations of craniopharyngioma usually result from partial or complete pituitary hormonal deficiencies. Growth hormone deficiency, with resultant short stature in childhood, diabetes insipidus, and other anterior pituitary hormonal deficiencies are common. Compression of the pituitary stalk or damage to the dopaminergic neurons in the hypothalamus result in hyperprolactinemia, which sometimes leads to misdiagnosis of a craniopharyngioma as a lactotroph adenoma. Although imaging may not easily distinguish the two lesions,20 a highly asymmetrical mass (especially with preferential posterior or dorsal extension) that does not shrink in response to dopamine agonist treatment should arouse suspicion of craniopharyngioma. A decrease in serum prolactin in response to dopamine agonist treatment, however, does not distinguish between the two. Thus craniopharyngioma may mimic a lactotroph adenoma in imaging, presence of hyperprolactinemia, and response of hyperprolactinemia to dopamine agonist treatment.
The treatment of these lesions is radical surgery, radiotherapy, or a combination of these modalities.21,22 In selected centers, stereotactic irradiation of the mass has been performed with some success. Nevertheless, regardless of which form of therapy is chosen, the ablation of the mass invariably results in anterior and/or posterior pituitary hormone deficits. Postoperative recurrence may occur in about a fifth of patients who undergo radical surgical excision,23 while no appreciable difference is noted in the outcome in those who undergo a subtotal surgical excision followed by radiotherapy. The presence of pure papillary squamous cellular elements may portend a higher surgical recurrence rate.24 The long-term effects of childhood irradiation for these tumors are considered elsewhere.
Meningiomas
These are usually benign and arise from the meninges anywhere within the head. About 20% arise near the sella,25 causing visual impairment and hormonal deficiencies. By MRI, meningiomas typically emit a low signal on T1-weighted images and a high signal on T2-weighted images and exhibit intense enhancement after gadolinium.
Pituicytomas
Pituicytomas are rare, benign tumors that arise from pituicytes,26 which are glial cells of the posterior pituitary. They have no hormonal secretory function and can be diagnosed only histologically by the characteristic histologic pattern of elongated cells in bundles and immunostaining for cell adhesion molecules.
Malignant Tumors
Germ Cell Tumors (Ectopic Pinealomas)
Suprasellar germ cell tumors27 usually occur through the third decade of life and are histologically and biologically similar to germ cell tumors in other anatomic locations, such as germinomas, teratomas, embryonal carcinomas, and choriocarcinomas. They may present with headache, nausea, vomiting, and lethargy (from increased intracranial pressure in patients with pineal lesions), diplopia, hypopituitarism or diabetes insipidus (with suprasellar tumors), and paralysis of upward conjugate gaze. If the tumor is in the pineal, imaging will show a mass in the third ventricle; if the tumor is in the infundibulum, it will be thickened.28 Serum concentrations of human chorionic gonadotropin beta (β-hCG), and/or alpha fetoprotein (AFP) may be increased. Although these lesions are highly malignant and metastasize readily, they are also highly radiosensitive.
Chordomas
Chordomas are slowly growing malignancies that arise from notochord remnants. Chordomas that arise in the clivus, the bone that is the base of the sella turcica, may present with headaches, visual impairment, and anterior pituitary hormonal deficiencies. MRI often shows a heterogeneous sellar mass associated with osteolytic bony erosion and calcification that may or may not be distinct from the normal pituitary. Histologically, they exhibit markers for epithelial cells, including cytokeratin and vimentin. After surgical excision, local invasion and recurrence commonly occur; mean patient survival is about 5 years. Rarely, chordomas become sarcomatous, sometimes after single fraction gamma- or proton-beam radiation,29,30 and then they are more aggressive.
Primary Lymphoma
Primary central nervous system (CNS) lymphoma sometimes involves the pituitary and hypothalamus. A review of 13 patients with pituitary involvement noted neurologic symptoms, including headaches and visual and oculomotor impairment, and/or deficiencies of anterior pituitary hormones and vasopressin.31 MRI shows a sellar mass with variable extrasellar extension.
Metastatic Disease
Metastases to the hypothalamus and pituitary gland occur most commonly with breast cancer in women and lung cancer in men but are encountered with other cancers.32,33 Symptoms include diabetes insipidus, anterior pituitary dysfunction, visual field defects, retro-orbital pain, and ophthalmoplegia.32,34 Reflecting that these are patients with metastatic disease, survival is not long; in 36 patients in one series, average survival was 6 months.33 Up to one quarter of patients with metastatic breast cancer have pituitary metastases. Interestingly, symptomatic pituitary metastases may be the presenting sign of previously undiscovered malignancy and even of malignancy of unknown origin. Although anterior pituitary failure is rare, an isolated metastatic deposit in the pituitary stalk without involvement of the anterior lobe may also present with pituitary failure. Metastases to the posterior pituitary lobe are far more common. About 15% of patients with diabetes insipidus harbor metastases from extrapituitary sources. Unfortunately, imaging of the pituitary mass does not distinguish these deposits from a pituitary adenoma unless extensive bony erosion is present. In fact, metastatic pituitary lesions may masquerade as a pituitary adenoma. In several instances, the diagnosis of pituitary metastasis will be made only by histologic study of the specimen removed at transsphenoidal surgery.
Pituitary Carcinoma
Carcinoma arising from anterior pituitary cells is quite rare. When it does occur, the malignancy can arise from any anterior pituitary cell type. Lactotroph,35 somatotroph, corticotroph,35 thyrotroph,36 and gonadotroph37 carcinomas have been reported. Diagnosis is made by finding a distant extracranial metastasis.
Infiltrative and Granulomatous Diseases
Infiltrative diseases, such as sarcoidosis and Langerhans cell histiocytosis, may cause a sellar mass and often cause widening of the pituitary stalk. Tuberculomas of the sellar region may occur as part of systemic infection or may be isolated to this region. Because these lesions primarily affect the hypothalamus and infundibulum, diabetes insipidus is common, whereas anterior pituitary hormone deficiencies are less frequently encountered. Infiltrative sarcoidosis of the hypothalamic-pituitary unit occurs in most patients with central nervous system sarcoid involvement.38 Typically these patients present with varying degrees of anterior pituitary failure with or without diabetes insipidus.
Abscess
Pituitary abscesses, which are rare, can occur in a normal or diseased pituitary gland. In immunocompromised subjects, they may be caused by fungi (Aspergillus, Nocardia, or Candida albicans) or Pneumocystis carinii. In a series of 24 patients, 16 presented with symptoms and physical findings consistent with a pituitary mass, while only 8 had features suggestive of infection, such as fever, leukocytosis, meningismus.39 MRI is usually unable to distinguish between pituitary abscess and pituitary adenoma, so most patients are diagnosed at the time of surgical exploration.
Etiology of Pituitary Adenomas
All pituitary adenomas appear to be true neoplasms, arising from a somatic mutation of a single progenitor cell that divides repetitively. The evidence for this view comes from studies that show that virtually all pituitary adenomas are monoclonal, that is, arise from a somatic mutation of a single cell. In one study of five women whose pituitary macroadenomas expressed some combination of FSHβ, LHβ, and α subunit and whose peripheral leukocytes were heterozygous for HPRT, the adenomas had predominantly one allele or the other, but not both40 (Fig. 9-1). This study suggests that gonadotroph adenomas arise from a somatic mutation of a single progenitor cell that then proliferates. Other studies present similar evidence that other types of pituitary adenomas are also clonal.41
FIGURE 9-1 Demonstration of clonality of pituitary adenomas. Southern blots from extracts of gonadotroph adenomas (c lanes) and peripheral leukocytes (d lanes) of five women who were heterozygous for the HPRT gene. The peripheral leukocytes from all five women expressed both alleles of the HPRT gene, but the adenomas expressed only one allele or the other. (From Alexander JM, Biller BMK, Bikkal H, Zervas NT, Arnold A, Klibanski A: Clinically nonfunctioning pituitary tumors are monoclonal in origin. J Clin Invest 86:336–340, 1990.)
Specific mutations have been identified in association with hereditary pituitary adenomas in multiple endocrine neoplasia type I (MEN 1), Carney complex, and familial isolated acromegaly associated with mutations of aryl hydrocarbon receptor interacting protein (AIP). In MEN 1,42 a mutation of the MEN1 gene results in decreased expression of the tumor suppressor gene menin and development of adenomas of the pituitary, parathyroids, and pancreas. All pituitary adenoma types can occur in MEN 1, most commonly lactotroph and somatotroph adenomas, and rarely including gonadotroph adenomas37,43 and those identified only as clinically nonfunctioning.44–46 In the Carney complex, about half the patients have germ line inactivating mutations in the regulatory subunit type I of the c-AMP-dependent protein kinase A gene (PRKARIA).47 The resulting phenotype consists of somatotroph adenomas, myxomas of the heart, skin, and breast, spotty skin pigmentation (multiple skin lentigines and blue nevi), schwannomas, ovarian cysts, and adrenal, testicular, and thyroid tumors. Mutations of AIP have been found in familial acromegaly in Finland48 but infrequently in familial acromegaly in other countries.
About 40% of somatotroph adenomas are associated with mutations of the gene encoding the alpha subunit of the G stimulatory protein (Gsα), and as a consequence, constitutively activating adenylyl cyclase and increasing cAMP, which is mitogenic to somatotroph cells, thereby resulting in somatotroph adenomas.49 Mutations that cause other pituitary adenomas, including gonadotroph adenomas, are not known. Investigators have searched for other mutations that might be causally related to development of other pituitary adenomas, but none of these has been clearly associated with the pathogenesis of any pituitary adenoma. Three genes have been identified that might be related to the pathogenesis of pituitary adenomas. One is the pituitary tumor transforming gene (PTTG), which was cloned from GH4 cells, a rat pituitary tumor cell line.50 It is overexpressed in the majority of human pituitary adenomas of all cell types compared with nonadenomatous pituitary tissue.51 Another is a truncated form of the fibroblast growth factor receptor 4, which has been identified in all types of human pituitary adenomas. A third is the MEG3 tumor suppressor gene, expression of which is selectively lost in nonfunctioning adenomas by hypermethylation.52
External hormonal stimulation from the hypothalamus is unlikely to be a primary cause of gonadotroph adenomas but might have a secondary effect on adenoma growth and probably has an effect on adenoma secretion, since administration of the GnRH antagonist Nal-Glu GnRH to patients who have gonadotroph adenomas and supranormal serum FSH concentrations lowers FSH levels to normal.53
Clinical Features
Clinically nonfunctioning sellar masses, by definition, do not cause florid syndromes of hormonal excess and as a result often grow unrecognized until they become so large as to cause neurologic symptoms, including abnormalities of vision and oculomotor function (see Table 9-2).
