Inflammatory Lesions

Inflammatory lesions of the sella are rare. Lymphocytic hypophysitis, the most common, is thought to

represent an autoimmune phenomenon and is seen usually in women during or after pregnancy, often in

association with other autoimmune disorders (Hashimoto thyroiditis, atrophic gastritis.) The gland is

enlarged and infiltrated with inflammatory cells and pituitary dysfunction may occur. Granulomatous

hypophysitis can arise from infections, that is, tuberculosis or fungal, or idiopathic granulomatous

inflammation, either alone or in association with sarcoidosis. The recent introduction of ipilimumab

antibody therapy for melanoma has led to the recognition of a presumed immune-mediated hypophysitis

associated with pituitary enlargement and dysfunction.13 Other uncommon types of hypophysitis include

xanthomatous, necrotizing, and IgG4 related.

MOLECULAR PATHOGENESIS

4 The molecular pathogenesis of pituitary adenomas remains unclear, although a number of possibilities

have been suggested.14,15 The majority of pituitary adenomas are monoclonal in origin.16,17 The

adenoma presumably arises from a single mutated cell, but the relative contributions of intrinsic genetic

events and stimulation by hypothalamic hormones and local growth factors remain to be determined.

Progression to malignancy with metastasis is rare, although local invasion is common. Genetic

mutations predisposing to the development of pituitary adenomas include mutations in the AIP gene

(aryl hydrocarbon receptor interacting protein) which has been found in some familial pituitary

adenoma cohorts as well as some sporadic adenomas, especially in young acromegalic patients. The

MEN1 (multiple endocrine neoplasia) gene is also associated with familial adenomas, but is uncommon

in sporadic disease, as is the GNAS mutation associated with McCune Albright syndrome. The PRKAR1A

gene encodes a type 1A regulatory subunit of protein kinase A. Inactivating mutations of this gene are

identified in 60% to 70% of patients with Carney complex, a condition of dominant inheritance, which

may lead to acromegaly as a result of somatotroph hyperplasia or adenoma, as well as a variety of

extrapituitary manifestations. Epigenetic modification has been suggested as a mechanism to influence

gene expression without alteration in the underlying genome. Altered expression of genes encoding

CDKN2A (cyclin-dependent kinase inhibitor), DAPK (death-associated protein kinase), FGFR2 (fibroblast

growth factor receptor 2), among others, have been associated with sporadic pituitary adenomas. Loss

of tumor suppressor genes may also be involved in adenoma pathogenesis. Loss of the GADD45y gene

expression occurs in the majority of human pituitary adenomas, and products of the AIP, PRKAR1A, and

MEN1 genes may also act as tumor suppressors, with loss of these products in familial syndromes

predisposing to the development of pituitary adenomas, in a “two-hit” model. Dysregulation of micro

RNAs, which can regulate translation of target mRNAs, has recently been found in pituitary adenomas,

and differential expression can be associated with specific tumor subtypes. It is unclear which, if any, of

these abnormalities are primary as opposed to epiphenomena in pituitary tumorigenesis.

ENDOCRINE EVALUATION

5 All patients with a pituitary mass require endocrine evaluation for pituitary hypofunction, and

patients with possible pituitary adenomas require evaluation for hypersecretory syndromes as well. This

is best done in conjunction with an endocrinologist experienced in the management of pituitary disease.

Pituitary Hypofunction (Hypopituitarism)

It is important to determine the presence of hypopituitarism, especially in patients requiring surgical

treatment, as unrecognized hypothyroidism or hypoadrenalism may have a profound effect on response

to anesthesia and complicate recovery from surgery. Determination of anterior pituitary dysfunction

requires measurement of free thyroxine (free T4) and thyrotropin (TSH), gonadal hormones (estradiol

and testosterone), as well as gonadotropins (LH and FSH), basal and stimulated cortisol levels, and

sometimes growth hormone levels and IGF1 (insulin-like growth factor 1) if clinically indicated. Central

(secondary) hypothyroidism is characterized by low free T4 levels in association with low or

inappropriately normal TSH. Central hypogonadism is characterized by low morning testosterone levels

in men, and low estradiol levels in women, associated with low or inappropriately normal FSH and LH.

Central hypoadrenalism is characterized by low morning cortisol levels in association with low or

inappropriately normal ACTH. Morning serum cortisol ≤3 mcg/dL is diagnostic of adrenal

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insufficiency, whereas morning serum cortisol ≥18 mcg/dL assures sufficient adrenal function.

Intermediate cortisol levels are indeterminate with regard to adrenocortical function and require further

evaluation, including stimulation with cosyntropin or insulin tolerance testing. Growth hormone levels

are normally pulsatile, which can make growth hormone insufficiency difficult to diagnose; it can be

presumed in the presence of multiple hormone insufficiencies, and confirmed by appropriate stimulation

testing, which can be undertaken after definitive treatment of the underlying pituitary lesion and

replacement of other pituitary hormone deficiencies have been implemented. Replacement therapy,

especially levothyroxine and glucocorticoid (prednisone or hydrocortisone), should be considered as

soon as the diagnosis of insufficiency is confirmed, especially in those patients who require surgery.

Glucocorticoid replacement should precede thyroid hormone replacement in order to avoid precipitating

adrenal crisis. Posterior pituitary dysfunction, typically diabetes insipidus (DI) is uncommon as a

presenting symptom; when seen in association with sellar mass, the diagnosis is unlikely to represent a

pituitary adenoma. Diabetes insipidus is characterized by polyuria/polydipsia, hyposthenuria and

tendency to hyperosmolar dehydration if access to water is limited or thirst is deficient; confirmation

may require a water deprivation test in uncertain cases. Hyponatremia may also occur in patients at the

time of their initial presentation as a consequence of the syndrome of inappropriate antidiuretic

hormone secretion (SIADH), central hypoadrenalism, or hypothyroidism.

Hypersecretory Syndromes

6 Pituitary adenomas may be associated with excess hormone secretion, giving rise to wellcharacterized clinical syndromes. It is important to recognize these preoperatively, especially since

surgical treatment in some instances is not first-line therapy. In particular, patients with prolactinsecreting pituitary adenomas may be offered a trial of medical therapy, as dopamine agonists are

effective in controlling tumor size and relieving mass effect.

Excess Prolactin (Prolactinomas)

Prolactin levels in women are physiologically increased during pregnancy, and are responsible for

lactation; prolactin levels in healthy men are typically low. Excess prolactin in women leads to the

syndrome of amenorrhea/galactorrhea, and hypogonadism with sexual dysfunction in men. Mildly

elevated prolactin levels may be related to medication effects (dopamine antagonists, e.g., psychotropic

medications), a microprolactinoma, or “stalk effect.” (Table 78-3). This phenomenon occurs from the

loss of tonic dopamine inhibition on the lactotrophs of the pituitary by any nonspecific mass

compressing the pituitary stalk. Thus a nonfunctioning tumor or other pituitary lesion of sufficient size

can lead to a moderately elevated prolactin level, usually less than 200 ng/mL, and this must be

distinguished from a prolactinoma, as treatments are potentially different. A large tumor in the setting

of a mildly elevated prolactin level likely represents “stalk effect” rather than a true prolactinoma; a

mildly elevated prolactin level in the setting of a microadenoma likely represents a true

microprolactinoma. Caution is advised in the interpretation of prolactin levels in patients with large

sellar masses. Giant macroprolactinomas may secrete prolactin exuberantly, giving rise to the “hook

effect,” an immunoassay artifact that occurs in the presence of very high serum concentrations of

prolactin, leading to substantial underreporting of prolactin levels. To avoid this artifact, prolactin

should be measured in serially diluted serum specimens in patients with large sellar lesions.

Excess Cortisol (Cushing Syndrome)

Hypercortisolemia of any cause is known as “Cushing syndrome.” These patients may present with a

wide variety of manifestations, including metabolic (central adiposity, glucose intolerance), catabolic

(muscle wasting, increased fracture risk, skin thinning, spontaneous ecchymoses, increased risk of

infection), cardiovascular (hypertension, thromboembolism, coronary artery disease), mineralocorticoid

(edema, hypokalemia), hypogonadal, hyperandrogenic (hirsutism, acne), and psychiatric symptoms.

There are a number of causes of Cushing syndrome, including (most commonly) iatrogenic, but

important neoplastic causes potentially requiring surgical treatment include pituitary adenomas, adrenal

adenomas/carcinomas, or the ectopic secretion of ACTH by a nonpituitary/adrenal source, usually

carcinoid tumors or small cell lung cancers. Approximately 70% to 80% of patients with noniatrogenic

causes of Cushing syndrome will have a pituitary adenoma (Cushing disease). The diagnosis of Cushing

disease can be difficult, and is best performed by an endocrinologist experienced in pituitary evaluation.

Hypercortisolemia is determined by measurement of 24-hour urine free cortisol levels, elevated serum

cortisol levels on dexamethasone suppression testing, and, more recently, by elevated late-night salivary

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cortisol levels. These tests help establish the presence of cortisol excess and differentiate between

Cushing syndrome and other states associated with high cortisol levels (Table 78-4). ACTH dependence

or independence is determined by the measurement of plasma ACTH levels; low ACTH levels (ACTH

independence) is seen with adrenal disease, as the increased cortisol levels are secreted independently

of central ACTH production, resulting in normal feedback inhibition of pituitary ACTH production. High

or inappropriately normal ACTH levels (ACTH dependence) are seen with pituitary or ectopic sources.

Normal ACTH levels in association with hypercortisolemia can also occur when diurnal variation is lost,

and typically point to a central rather than adrenal source. Dexamethasone suppression testing can be

performed to biochemically differentiate pituitary from ectopic sources. Classically, failure to suppress

cortisol levels with high-dose dexamethasone is associated with an ectopic source, though this may also

be seen with some pituitary macroadenomas. While pituitary MRI imaging may demonstrate an

adenoma, typically the microadenomas of Cushing disease are very small, and may not appear on MRI

in 30% to 40% of patients. In these cases confirmation of a pituitary source requires bilateral inferior

petrosal sinus sampling, where ACTH levels obtained from the inferior petrosal sinuses (both before and

after the intravenous administration of corticotropin-releasing hormone [CRH]) are compared to levels

obtained in the vena cava; a central-peripheral ACTH ratio of greater than 3:1 after the administration

of CRH is considered diagnostic of a central source, even in the absence of tumor visualization on

MRI.18

Table 78-3 Causes of Hyperprolactinemia

Table 78-4 Conditions Associated with Cortisol Excess

Excess Growth Hormone (Acromegaly)

Excess growth hormone secretion by a pituitary adenoma in childhood, prior to epiphyseal closure,

leads to gigantism, while growth hormone excess in adulthood leads to acromegaly. Adult patients will

typically report increased ring and shoe size, dental and jaw abnormalities with malocclusion,

coarsening of facial features (often falsely attributed to aging), headache, hoarseness, skin tags,

increased sweating, carpal tunnel syndrome, arthralgias, frequent snoring, and sleep apnea. Because

these changes occur slowly over time, diagnosis can be delayed, and these tumors are often larger and

invasive at the time of detection. Systemic changes include glucose intolerance or frank diabetes

mellitus, hypertension, and cardiomyopathy. There is an increased risk of colon polyps, and possibly

colon and thyroid cancer. Acromegalic patients have a mortality risk on the order of 2 to 3 times that of

the general population, if growth hormone excess is not adequately controlled. Many of these changes

are reversible with successful control of the disease, but skeletal abnormalities are not. Because growth

hormone secretion is pulsatile, random growth hormone measurements are not diagnostic. IGF1

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(somatomedin C) is a protein produced mostly in the liver in response to growth hormone levels over

time; it acts to integrate the pulsatile growth hormone levels and serves as the best single indicator of

disease activity. IGF1 assays are technically challenging and require gender and age adjustment, as

growth hormone levels increase during childhood and adolescent development and decrease with aging,

and are higher in males than females. Because growth hormone is physiologically suppressed by a

glucose load, glucose-suppressed growth hormone levels have been used as an indicator of disease

activity, since acromegalic patients fail to suppress and may paradoxically increase. The criterion for

adequate suppression has varied with the available growth hormone assay; current best available assays

require suppression to at least GH <1 ng/mL (ideally below 0.4 ng/mL). Growth hormone

measurements over time (day curve) have also been used in diagnosis, but are cumbersome to

determine in an outpatient setting.

TSH Adenomas

While immunocytochemical staining for TSH is not uncommon, secretion of active thyrotropin in excess

leading to central hyperthyroidism is rare. These patients will manifest the clinical syndrome of

hyperthyroidism with attendant systemic manifestations. The majority of these tumors are

macroadenomas and may therefore be associated with mass effect. Biochemically, they demonstrate a

nonsuppressed (inappropriately normal or increased) TSH level, in the setting of elevated thyroid

hormones, that is, one does not see the feedback-inhibited TSH levels associated with primary

hyperthyroidism. This syndrome needs to be distinguished from resistance to thyroid hormone which

can lead to a similar hormone profile.

Endocrine Evaluation of a Pituitary “Incidentaloma”

With the widespread availability of MRI imaging, it is not uncommon for the radiologist to report the

incidental finding of a pituitary mass. The endocrine evaluation requires screening of pituitary hormone

levels to determine possible hypo- or hyperfunction, which will help to guide further therapy.

Physiologic pituitary hypertrophy can be difficult to distinguish from a true pituitary adenoma, but

requires an appreciation of the clinical setting to guard against unnecessary surgical intervention.

Typically, adolescents, especially adolescent females, can demonstrate physiologic hypertrophy during

puberty and for a few years thereafter, and women during pregnancy or during lactation can

demonstrate physiologic enlargement of the gland from lactrotroph hyperplasia. Patients with

unrecognized severe primary hypothyroidism can present with pituitary enlargement, sometimes

striking, as a result of thyrotroph hyperplasia, which resolves with appropriate thyroid replacement.

Rarely, ectopic secretion of growth hormone releasing hormone or corticotropin releasing hormone may

lead to somatotroph or corticotroph hyperplasia, respectively. All these conditions need to be

distinguished from true pituitary adenomas.

NEUROLOGIC EVALUATION IN PITUITARY ADENOMAS

The primary neurologic manifestation of a pituitary mass is ophthalmologic, from compression of the

optic nerves or chiasm traveling through the suprasellar cistern. Because the ipsilateral retinal ganglion

cell axons cross in the optic chiasm en route to the contralateral occipital cortex, the pathognomonic

finding on visual field examination is a bitemporal hemianopsia (“pie-in-the-sky”). The chiasm may

sometimes be associated with a relatively short intracranial optic nerve segment (“prefixed”) or a

relatively long intracranial optic nerve segment (“post fixed”). Depending upon the relative position of

the tumor and chiasm, compression may also lead to uni- or bilateral optic nerve dysfunction, or

compression of an optic tract, with a homonymous hemianopsia. Patients may sometimes report

decreased acuity, although central vision is usually preserved unless compression is severe. A unilateral

decrease in color vision is a sensitive sign of an early optic neuropathy, as is an afferent pupillary defect

(Marcus Gunn pupil). This can be demonstrated by the “swinging flashlight test,” where light shown

into the affected eye leads to a paradoxical increase in pupillary size, as the ipsilateral pupilloconstrictor fibers have been damaged by ipsilateral optic nerve compression and transmit relatively

decreased retinal activity. Although pituitary adenomas will often invade the cavernous sinus and

displace the cranial nerves within, cranial nerve dysfunction other than optic is uncommon. When

present, and especially if of sudden onset, one should suspect a rapidly expanding mass, that is, pituitary

apoplexy, or a more aggressive tumor, for example, a malignancy. Similarly, pituitary adenomas will

often circumscribe but rarely constrict the cavernous carotid artery or cause neurovascular dysfunction;

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