Sellar Masses

Are You Sure the Patient Has a Sellar Mass?

Sellar masses are common. Incidental sellar masses are present in about 10-15% of the adult population; however, the vast majority of incidentally found lesions are relatively small (less than 10 mm in greatest diameter). Approximately 90% of sellar masses are pituitary adenomas. However, there is a large number of additional diagnostic possibilities to be considered.

A systematic approach is advisable in order to evaluate the presence of mass effect, pituitary hormone excess or deficiency, or the possibility of systemic disease affecting the sella and reach a presumptive diagnosis preoperatively, which will help guide management.

A multidisciplinary approach is generally optimal in the care of these patients. Depending on patient characteristics, input from an expert pituitary neurosurgeon, a neuroradiologist, a neuro-oncologist, and a radiation oncologist may be required, in addition to evaluation by an endocrinologist with interest in pituitary disorders.

Symptoms and signs

Local mass effect: Larger lesions, generally exceeding 10 mm in diameter (e.g., pituitary macroadenomas), may impinge upon surrounding structures, leading to a variety of symptoms and findings. Such manifestations may include vision loss as a result of impingement on the optic apparatus (commonly bitemporal hemianopsia as a result of optic chiasm compression), headache (as a result of pressure exerted on the dura diaphragm or other structures), diplopia (as a result of compression of cranial nerves (III, IV, or VI), face pain or numbness (as a result of compression of trigeminal nerve), seizures (e.g., partial complex seizures as a result of temporal lobe compression), and hydrocephalus (as a result of compression on the third ventricle).

Manifestations of pituitary hormone excess: Functioning pituitary adenomas (or, rarely, hyperplasia of pituitary somatotrophs or corticotrophs caused by ectopic secretion of GHRH or CRH, respectively) are associated with specific syndromes of hormone excess, including:

• Prolactin-secreting pituitary adenomas may lead to hypogonadism in patients of both genders, infertility, and galactorrhea in women (the latter is very rare in men).

• Growth hormone-secreting pituitary adenomas are associated with gigantism (when occurring in childhood or adolescence) and acromegaly (in adults).

• Corticotropin-secreting pituitary adenomas are associated with pathological hypercortisolism. The term Cushing’s disease is used specifically for patients with Cushing’s syndrome of pituitary origin.

• Thyrotropin-secreting pituitary adenomas are associated with hyperthyroidism. Extrathyroidal manifestations of Graves disease (orbitopathy, pretibial myxedema, acropachy) are generally absent in these patients.

• Gonadotropin-secreting pituitary adenomas are generally hormonally inefficient and are usually not associated with clinical manifestations of hormone excess. However, in rare cases, these tumors may secrete sufficient intact gonadotropins to cause clinical symptoms (precocious puberty in children; oligomenorrhea, polycystic ovaries, and infertility in women).

• The syndrome of inappropriate ADH secretion may occur in patients with large sellar masses preoperatively, as well as in all patients undergoing pituitary surgery.

Manifestations of pituitary hormone deficiency: Larger lesions, generally exceeding 10 mm in diameter (e.g., pituitary macroadenomas), may compress the normal pituitary gland, leading to anterior hypopituitarism (growth hormone deficiency, central hypogonadism, central hypothyroidism, central hypoadrenalism).

Very large or infiltrative lesions may also lead to central diabetes insipidus. Lesions involving the pituitary infundibulum (stalk) may lead to anterior hypopituitarism and diabetes insipidus, regardless of size.

Evidence of systemic disease affecting the sella should be sought in patients with suspected systemic disorders that might involve the pituitary and/or hypothalamus. Examples include:

• Patients with sarcoidosis may be noted to have a variety of skin rashes, ocular inflammation, and lacrimal gland enlargement.

• Evaluation of patients with Langerhans cell histiocytosis may reveal skin rashes, bone lesions (either painful or asymptomatic), or lung or other solid organ involvement.

• Patients with systemic infections affecting the pituitary may have systemic manifestations peculiar to the infection (e.g., tuberculosis or Whipple’s disease).

• Patients with incidentally found sellar masses may have unrelated complaints (e.g., vertigo or head injury) and can be truly asymptomatic with regard to the sellar mass.

Epidemiology

Sellar masses may occur at any age and patients of either gender. However, the relative frequency of specific pathologies varies by age and gender:

• In children and adolescents with a sellar mass, craniopharyngiomas are the most common underlying pathology. In contrast, pituitary adenomas account for the vast majority of sellar masses in adults.

• Among pituitary adenomas, clinically nonfunctioning pituitary tumors become more common with advancing age in adults.

• Craniopharyngiomas show a bimodal age distribution (childhood/adolescence and in the sixth decade of life).

• Germ cell tumors almost always present in the first two decades of life.

• Meningiomas are rare in childhood, but increase in incidence during adult life. They are much more common in women (2:1 female-to-male predominance).

• Some medications, including alpha interferon and ipilimumab (CTLA-4–blocking antibody), have been associated with hypophysitis.

Pathophysiology

Nearly all pituitary adenomas are monoclonal and most appear to be sporadic. Several genes and their transcripts have been implicated in pituitary tumorigenesis, based on abnormal expression patterns, including PTTG, noggin gene, GADD45 gamma, and MEG3.

Approximately 5% of patients with pituitary adenomas may have familial conditions predisposing them to tumor formation, frequently occurring at a younger age than sporadic cases. These familial syndromes are transmitted as autosomal dominant traits and involve germline inactivating mutations of putative tumor suppressor genes.

Known familial syndromes include MEN-1 (associated with mutations of the gene encoding menin), MEN-4 (involving mutations in the CDKN1B gene, encoding p27 [Kip]), Carney complex (associated with mutations in the PRKAR1A gene in most patients), and familial isolated pituitary adenoma [involving mutations of the gene encoding the aryl hydrocarbon receptor interacting protein (AIP) in 15-40% of cases].

What Else Could the Patient Have?

Pituitary adenomas (almost always benign), including functioning tumors (secreting prolactin, growth hormone, corticotropin, thyrotropin, gonadotropins, plurihormonal tumors) or clinically nonfunctioning (including most gonadotropin-expressing tumors, null adenomas) (Figure 1).

Figure 1.

Other tumors, including germ cell tumors (germinomas, teratomas, and others), meningiomas, gliomas, pituicytomas, chordomas, chondrosarcomas, lymphomas, and metastases (Figure 2 and Figure 3).

Figure 2.

Figure 3.

Congenital lesions, including tuber cinereum hamartomas.

Cystic lesions, including Rathke’s cleft cysts, craniopharyngiomas, dermoid cysts, epidermoid cysts, and arachnoid cysts.

Vascular lesions, including aneurysms and cavernous sinus hemangiomas.

Hypophysitis, including lymphocytic, granulomatosis (idiopathic or associated with sarcoidosis, Langerhans cell histiocytosis, or Wegener’s granulomatosis), necrotizing and xanthomatous varieties. Other varieties include ipilimumab-induced or alpha interferon–induced hypophysitis, as well as IgG4-related hypophysitis (Figure 4).

Figure 4.

Infections, including bacterial (abscess, Whipple’s disease), mycobacterial (tuberculosis), and fungal pathogens.

Diffuse pituitary enlargement, including physiological (lactotroph) hyperplasia in pregnancy and thyrotroph hyperplasia in severe primary hypothyroidism. In addition, ectopic hormone secretion may lead to hyperplasia (somatotroph hyperplasia as a result of ectopic GHRH secretion or corticotroph hyperplasia as a result of ectopic CRH secretion).

Empty sella

Other clinical manifestations

Uncommonly, patients with a pituitary adenoma (generally macroadenoma) may present with acute, severe headache, frequently associated with additional evidence of mass effect (acute vision loss or diplopia) as a result of hemorrhage and/or infarction within the sellar mass, a condition termed pituitary apoplexy. These patients may also have fever, neck stiffness, or impaired level of consciousness. In these patients, subarachnoid hemorrhage and meningitis need to be considered as alternate diagnostic possibilities (Figure 5).

Figure 5.

In contrast, dysfunction of cranial nerves III, IV, and VI is very uncommon in patients with pituitary adenomas in the absence of pituitary apoplexy. The presence of these should raise suspicion for other sellar or parasellar pathologies, such as meningiomas or metastases.

Key Laboratory and Imaging Tests

Imaging studies are essential to characterize a sellar lesion and may provide important diagnostic information noninvasively:

An MRI examination is generally the best study to characterize the majority of sellar masses. A pituitary protocol MRI examination, which includes focused views of the sella using T1-weighted coronal and sagittal sequences, both before and after gadolinium contrast administration, is needed to adequately visualize the sella. In addition, T2-weighted images can provide helpful diagnostic information.

Pituitary microadenomas appear as hypodensities on contrast-enhanced T1-weighted images. They may be missed, if gadolinium contrast is not used.

Macroadenomas generally grow slowly, leading to sellar floor remodeling and expansion. Pituitary macroadenomas frequently enhance heterogeneously after contrast administration. Involvement of the cavernous sinuses and impingement on the optic apparatus may be best appreciated on contrast-enhanced images (see Figure 1).

On unenhanced T1-weighted images, bright lesions indicate the presence of blood, cystic fluid of high protein content, or fat. Bright lesions on T2 sequences (similar to CSF in appearance) are cystic.

Meningiomas generally reveal a “dural tail,” which is characteristic (but not pathognomonic) of these lesions. These tumors typically enhance brightly and homogeneously after contrast administration (see Figure 3).

Lesions predominantly affecting the infundibulum/stalk can be inflammatory (hypophysitis), infectious, cystic (craniopharyngiomas or Rathke’s cleft cysts), or neoplastic (germ cell tumors, meningiomas, gliomas, lymphomas, metastases from a lung or breast primary malignancy) (Figure 2).

A CT examination of the sella (using a dedicated pituitary protocol) can be helpful in specific situations, including the demonstration of bone erosions, sellar mass calcifications (frequently present in craniopharyngiomas), and hemorrhage within a sellar lesion.

Laboratory testing is needed in every patient with a sellar mass to evaluate the presence of pituitary hormone excess. Patients with larger lesions (>10 mm in diameter) or lesions involving the infundibulum/stalk (regardless of size) should also be evaluated for pituitary hormone deficiency:

Evaluation of pituitary hormone excess includes assays of serum prolactin, IGF-I (to examine possible GH excess), TSH, and free T4 (to check for central hyperthyroidism). A variety of tests can be used to examine the presence of hypercortisolism, including assays of late-night salivary cortisol, 24-hour urine-free cortisol, and the overnight (1 mg) dexamethasone suppression test.

Among patients with sellar masses, very high serum prolactin levels (>200 ng/ml) generally indicate prolactin secretion by the tumor (i.e., the presence of a prolactinoma). Lesser degrees of hyperprolactinemia in patients with presumed macroadenomas may likely indicate the presence of “stalk effect” (stalk compression by a nonfunctioning lesion).

In patients with suspected macroadenomas, prolactin should be measured after serial specimen dilutions to examine the possibility of a “hook effect,” which may occur in patients with extremely high serum prolactin levels that exceed the ability of dual antibody assays (capture and reporter antibodies) to “sandwich” the antigen (prolactin), leading to artifactually low reported prolactin levels. Measuring prolactin in dilution is essential to avoid misclassifying a macroprolactinoma as a nonfunctioning lesion.

Evaluation of anterior pituitary hormone deficiencies includes assays of early morning serum cortisol (or stimulated serum cortisol in response to cosyntropin or insulin-induced hypoglycemia), free T4, early morning serum testosterone (in men), or menstrual history (in women). Serum IGF-I and IGF BP -3 levels are very helpful in screening for GH deficiency in children or adolescents but are of limited diagnostic value in adults.

Random levels of corticotropin, thyrotropin, or gonadotropins are not helpful as diagnostic tests for the respective pituitary deficiencies. However, these tests are helpful in distinguishing between central (pituitary) and primary (target gland) hypofunction.

Stimulation testing is needed to confirm the presence of GH deficiency and may also be needed to establish the presence of hypoadrenalism. It should be noted that cosyntropin stimulation testing can be falsely normal for several weeks after the acute onset of corticotropin deficiency (as is the case in patients undergoing pituitary surgery).

Evaluation of posterior pituitary function includes tests of serum sodium and osmolality as well as urine osmolality (or specific gravity). If the results of these tests are not diagnostic when performed at baseline, these analytes can be measured in response to water deprivation in a monitored setting, in order to establish the diagnosis of suspected diabetes insipidus.

Other Tests That May Prove Helpful Diagnostically

Serum calcium may be measured in patients with (presumed) pituitary adenomas to screen for primary hyperparathyroidism, a constellation suggestive of the MEN 1 syndrome.

Both hCG and alpha fetoprotein (AFP), measured in serum and CSF, may be of diagnostic value in patients with suspected germ cell tumors. However, the absence of these tumor markers does not exclude the diagnosis of germ cell tumors, as many are nonsecreting.

Serum angiotensin-converting enzyme levels can be measured in serum and CSF of patients with suspected sarcoidosis (elevated in about 65% of these patients).

Serum IgG4 levels are helpful in patients with IgG4-related hypophysitis.

Antineutrophil cytoplasmic antibodies (ANCA), including c-ANCA, are very helpful in patients with suspected Wegener granulomatosis (elevated in >90% of patients with this condition).

Management and Treatment of the Disease

Glucocorticoid replacement therapy should be promptly initiated in patients with central hypoadrenalism. Stress-dose glucocorticoid coverage should urgently be administered in acutely ill patients. In particular, patients with hemodynamic instability and suspected hypoadrenalism should receive glucocorticoid replacement without delay, before biochemical confirmation of adrenal insufficiency is obtained.

Pharmacologic doses of glucocorticoids are generally recommended in patients presenting with acute mass effect (e.g., acute vision loss as a result of hemorrhagic infarction within a pituitary macroadenoma, termed pituitary apoplexy, as described below).

Presumed prolactin-secreting pituitary adenomas can be treated medically with a dopamine agonist, including bromocriptine or cabergoline (or quinagolide, available in some countries), to restore gonadal function and relieve/prevent mass effect. Indications for medical therapy include the presence of hypogonadism and/or infertility, bothersome galactorrhea, the presence of a macroprolactinoma, or tumor growth.

Sex steroid replacement therapy may be used as an alternative option in patients with stable microprolactinomas and hypogonadism who are not seeking fertility. Asymptomatic patients with stable microprolactinomas can be followed expectantly without specific therapy. On the other hand, patients who have indications for treatment, but do not respond or are intolerant of medical therapy should be considered for surgery.

Pituitary surgery is the primary treatment modality for most sellar masses (other than prolactinomas). The transsphenoidal route is preferred in patients with lesions accessible via this approach, as it is associated with less morbidity than craniotomy. In patients with sellar masses, indications for surgery include the presence of mass effect (compression of the optic apparatus leading to visual field defects, diplopia, suspected pituitary apoplexy), hormone excess other than prolactin, sellar mass growth (even in asymptomatic patients), and the need to establish a tissue diagnosis.

Persistent headache and hypopituitarism are relative indications for surgery in patients with presumed clinically nonfunctioning macroadenomas, as they are not consistently improved by surgical intervention.

Asymptomatic patients with presumed clinically nonfunctioning pituitary macroadenomas may also be considered for pituitary surgery, particularly those with lesions abutting the optic apparatus, provided that their general medical status does not excessively increase surgical risk.

Medical therapy options are available for patients with acromegaly/gigantism, including those who do not achieve a remission postoperatively, and can also be considered as the primary therapeutic therapy in select patients. Somatostatin receptor ligands (octreotide, octreotide LAR, lanreotide depot), pegvisomant (growth hormone receptor antagonist), and cabergoline may all be considered.

Medical therapies may also be advised in patients with Cushing disease who do not achieve a remission postoperatively (and are commonly used to bridge patients who are awaiting the effects of radiation therapy). In this setting, agents potentially used include those that inhibit adrenal steroidogenesis (ketoconazole, metyrapone, mitotane, or etomidate), those that act directly on pituitary corticotropinomas (cabergoline or pasireotide), as well as a glucocorticoid receptor antagonist (mifepristone).

Thyrotropinomas not adequately treated with surgery may frequently respond to somatostatin receptor ligands (octreotide, octreotide LAR or lanreotide depot).

Radiation therapy to the sella can be administered as either conventional fractionated therapy or stereotactic radiation therapy (using gamma knife, linear accelerator or proton beam). The latter is frequently administered in a single fraction (“radiosurgery”). This is possible for lesions that are at least 3 mm away from the optic apparatus.

Radiation therapy is frequently advised as second-line therapy in patients with nonfunctioning lesions (pituitary adenomas, craniopharyngiomas, meningiomas) persisting or recurring postoperatively or patients with Cushing disease failing surgery. Radiation therapy can also be used as the primary treatment modality in patients with radiosensitive lesions (e.g., germinomas, some metastases) or surgically inaccessible tumors (e.g., cavernous sinus meningiomas).

Radiation therapy is highly effective in controlling tumor growth. However, it is associated with significant (~70%) risk of anterior hypopituitarism.

Temozolomide is an alkylating agent that has been successfully used to control the growth of locally aggressive pituitary adenomas refractory to surgery and radiation therapy. Other antineoplastic chemotherapy agents may be used to treat specific tumors (e.g., carboplatin and etoposide in patients with germ cell tumors).

Other therapies

Glucocorticoid replacement is essential in every patient with central hypoadrenalism. Thyroid hormone replacement should only commence after glucocorticoid replacement has been implemented.

In patients undergoing pituitary surgery, pituitary function should be reassessed postoperatively (generally around 6 weeks) and the need for ongoing replacement therapies reevaluated. Pituitary function may improve in up to 40% of patients undergoing resection of a pituitary tumor but may also deteriorate in 5-10% of patients postoperatively.

Desmopressin therapy should be administered to patients with central diabetes insipidus. Close monitoring of serum sodium is recommended in postoperative patients and the ongoing need for desmopressin therapy reevaluated on a daily basis during the first 2-3 weeks, as diabetes insipidus may be transient or followed by hyponatremia (the latter occurring as a result of inappropriate ADH secretion, unreplaced hypoadrenalism, or hypothyroidism).

Sex steroid and growth hormone replacement therapies are generally deferred until after definitive therapy of the sellar mass has been implemented, and the presence of respective hormone deficiencies established. In particular, it is advised that growth hormone replacement be initiated only after stability of the appearance of the sella is demonstrated on follow-up imaging.

Active malignancy is an absolute contraindication to growth hormone replacement. In patients whose malignancy is in remission, growth hormone replacement may be initiated with extreme caution, and only after their oncologist has been consulted and is in agreement.

Prognosis

The natural history of pituitary masses is likely quite diverse, depending on the nature of underlying pathology. It may be noted that the natural history of most sellar masses is incompletely understood, as there are relatively limited data on patients with sellar masses followed expectantly (with the exception of asymptomatic microprolactinomas).

Small case series of patients with incidentally found sellar lesions (most of which are likely to be pituitary adenomas) suggest that microincidentalomas (lesions less than 10 mm in diameter) may enlarge in approximately 10% of patients, whereas macroincidentalomas (lesions exceeding 10 mm in diameter) may grow in about 20% of cases.

The goals of therapy are individualized but may broadly include relief of mass effect, clinical and biochemical remission of hormone excess, restoration, and/or preservation of pituitary function, while minimizing complications and any possible negative effects of the underlying condition on life expectancy and quality of life.

Surgery provides the best chance of meeting these goals for most patients with pituitary masses (with the exception of patients with presumed prolactinomas, which generally respond well to medical therapy). However, persistent or recurrent disease may occur postoperatively, requiring life-long follow-up (imaging and laboratory testing). The recurrence risk may vary significantly depending on the underlying pathology, size, and location of the sellar lesion and surgical expertise.

Patients with functioning sellar lesions, including acromegaly and Cushing disease, have increased mortality risk. However, remission of these conditions appears to mitigate the excess mortality associated with growth hormone or cortisol excess, respectively.

What if?

The presence of central diabetes insipidus occurring in a patient with a sellar mass prior to any pituitary surgery strongly suggests that the sellar mass is not a pituitary adenoma.

It is advisable to review patients’ older photographs at time of physical examination. Changes in facial appearance or features may provide subtle, yet important clues to the presence of growth hormone or cortisol excess.

Central hypoadrenalism should always be sought and either ruled out or treated with physiologic (replacement) doses of glucocorticoids, before thyroid hormone replacement is advised. This is essential to avert precipitating adrenal crisis, which may occur by introducing thyroid hormone replacement in a patient with untreated central adrenal insufficiency.

Unreplaced glucocorticoid and thyroid hormone deficiencies decrease free water clearance by the kidneys and may prevent the development of polyuria in patients with ADH deficiency. As a consequence, the institution of glucocorticoid and thyroid hormone replacement therapies in patients with panhypopituitarism may unmask previously latent central diabetes insipidus, precipitating the onset of hyposthenuric polyuria.

Follow-up

Regular, pituitary protocol MRI examinations are advised in all patients with sellar masses. The frequency of MRI examinations depends on the underlying pathology. It may be noted that the optimal frequency of follow-up imaging has not been determined in prospective studies.

Incidental sellar lesions thought to represent nonfunctioning adenomas and are being followed expectantly may be imaged at 6 months and annually thereafter for 4-5 years, with less frequent imaging thereafter, if stable.

Patients undergoing pituitary surgery should generally have postoperative MRI examinations at 6-12 weeks, with subsequent MRI studies obtained at 6 months, and then annually thereafter for 4-5 years. Subsequently, MRI examinations may be performed every 2-3 years in patients with stable appearance of the sella.

After undergoing pituitary surgery, patients should be monitored (including assessment of fluid balance, serum sodium, and urine specific gravity or osmolality) to detect the possible development of diabetes insipidus, and should have frequent monitoring of serum sodium for about 2 weeks after surgery in order to detect the possibility of hyponatremia (occurring as a result of the syndrome of inappropriate ADH secretion, hypoadrenalism, or hypothyroidism).

Preemptively instituted glucocorticoid replacement is advised after pituitary surgery, until sufficiency of pituitary-adrenocortical function is assured. Full evaluation of pituitary function should be performed postoperatively (generally around 6 weeks after surgery) to examine whether pituitary function is intact, and establish if biochemical remission of disorders associated with hormone excess has occurred.

Patients with functioning pituitary adenomas require life-long periodic evaluation to detect possible biochemical recurrences.

All patients who have received radiation therapy to the sella should have life-long periodic assessment of pituitary function to detect the possible development of anterior hypopituitarism, which eventually occurs in approximately 70% of irradiated patients.

Patients with persistent or recurrent sellar masses after initial surgery may require reoperation, radiation therapy or medical therapy as already outlined.

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