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The pituitary lies in the sella turcica, a concavity in the sphenoid bone. Its stalk,
which contains the pituitary portal veins and neuronal processes, passes through the
diaphragma sella, just above which pass the optic nerves (Figure 1). The cavernous sinuses
form the lateral borders of the sella, and contain within them the internal carotid
arteries, cranial nerves III, IV and VI, and the ophthalmic and maxillary divisions of
cranial nerve V.
Fig. 1 Anatomic relationships of the pituitary gland. A coronal view through the
sella turcica shows the pituitary gland, its stalk and the relationship to
surrounding structures including the cavernous sinuses, carotid arteries and
cranial nerves II, III, IV, V1, V2 and VI. (Figure from Oyesiku N: Assessment of
Pituitary Function, in Rengachary S, Ellenbogen R (eds): Principles of
Neurosurgery. New York, Elsevier Mosby, 2005, pp 559-591)(30)
Because of its diverse array of functions as well as the multiple structures in close
proximity to the gland, tumors or abnormalities of pituitary function can present in many
different ways. Disorders can lead to an excess or deficiency of pituitary hormones, mass
effect from tumors can lead to compression of the pituitary stalk or adjacent structures,
and lesions may cause a blockage of the blood supply to the gland. Therefore, a thorough
assessment of the pituitary requires clinical examination for signs of hormonal
abnormalities, endocrine evaluation of pituitary and related target-organ hormones, and
ophthalmologic evaluation to assess for damage to the adjacent cranial nerves. These
evaluations not only help to define the pathology prior to treatment, but they can be used
to assess the effects of surgery, radiation or medical treatment. Here, we will discuss details
the endocrine evaluations needed to determine pituitary function.
Anterior Pituitary Hormones
Six hormones are produced in the anterior pituitary by five distinct cell types.
Lactotroph cells make prolactin (PRL), somatotroph cells produce growth hormone
(GH), corticotrophs secrete adrenocorticotrophic hormone (ACTH), thyrotrophs make
thyroid-stimulating hormone (TSH), and gonadotrophs produce follicle-stimulating
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hormone (FSH) and luteinizing hormone (LH). The secretion of these hormones is
regulated by complex feedback controls from the hypothalamus and target glands
(Figure 2).
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PRL is secreted episodically, peaking 13-14 times per day, with an interpulse interval
of about 90 minutes. Small post-prandial rises can be seen, secondary to central
stimulation from the amino acids in food (9). During pregnancy, estrogen stimulates
lactotroph hyperplasia, leading to hyperprolactinemia. The effects of PRL on the breasts
are blocked until after delivery, at which time PRL initiates lactation. Within 4-6
months after delivery, basal PRL levels return to normal (35).
Prolactin Deficiency
Hypopituitarism leads to a decrease in PRL release. A blunted PRL response in a TRHstimulation test, with a less than 2-fold increase over basal levels, is evidence of
inadequate lactotroph reserve which may occur with hypopituitarism.
Insufficient PRL can lead to a failure of lactation. This may be an early indication of
peripartum pituitary necrosis, or Sheehan's syndrome. Lymphocytic hypophysitis is an
autoimmune disorder which usually occurs during or immediately following pregnancy.
Transient hyperprolactinemia occurs during its active phase, followed by hypopituitarism
and hypoprolactinemia.
Prolactin Excess
Multiple causes can lead to the over-stimulation of prolactin release and elevated serum
PRL levels. Hyperprolactinemia may be due to: 1. excess autonomous production,
such as from a pituitary prolactinoma; 2. decreased hypothalamic production of
dopamine or blockage of delivery of dopamine to the pituitary, such as from a
hypothalamic tumor, drugs that inhibit dopamine production, interruption of the
portal venous system in the stalk from a pituitary tumor or aneurysm, or following
pituitary irradiation; 3. inhibition of dopamine activity on lactotrophs, such as from
phenothiazines that block the interaction of dopamine from its receptors; or 4. overstimulation of PRL by estrogens or opiates. Non-hypothalamic-pituitary causes may be
responsible as well, including pregnancy, polycystic ovarian syndrome or primary
hypothyroidism. Physiologic, transient hyperprolactinemia occurs with exercise, stress,
nipple stimulation, sexual intercourse, and breast-feeding.
Women with hyperprolactinemia generally present with amenorrhea, galactorrhea,
diminished libido and infertility. Gonadal deficiency and decreased estrogen secretion can
lead to osteoporosis. Hyperprolactinemia in men generally manifests as decreased
libido, impotence and decreased sperm count leading to infertility.
Workup
Laboratory tests for suspected hypo- or hyperprolactinemia include serial
measurements of basal, resting serum PRL levels by radioimmunoassay. Normal values
are gender-specific, and peak values occur during the late hours of sleep (37). PRL is
secreted episodically, so random levels may be above or below normally-accepted
limits. Because of this variability, minimally elevated levels should be confirmed from
several samples, or from a pooled sample. In normal subjects, serum PRL levels range
from 5-20 ng/mL.
PRL deficiency of <2 ng/mL is generally associated with severe hypopituitarism,
though may be due to PRL-lowering medications. A PRL level of more than 200 ng/mL
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is nearly diagnostic of a prolactinoma (33). Prolactinomas are the most common type of
hormone-secreting pituitary tumor, comprising almost 30% of all pituitary tumors.
Pregnancy must be excluded, however, as PRL levels reach 100-250 ng/mL by the third
trimester (34).
An intermediate degree of PRL elevation, 20-200 ng/mL, can result from a number of
different conditions. Medications can cause PRL levels of more than 100 ng/mL.
Compression of the pituitary stalk from a pituitary tumor rarely causes PRL to rise above
100 ng/mL, but elevations to more than 200 ng/mL can occur. This increase in PRL due
to compression of the stalk is known as the stalk effect. Stimulation of PRL secretion
with a TRH-stimulation test can suggest the presence of a prolactinoma. In normal
subjects, intravenous (IV) administration of 200-500 g of TRH should lead to a 3 to 5fold increase in serum PRL level within an hour. Patients with a prolactinoma will
often have a blunted response of less than a 2-fold increase, due to their limited
lactotroph reserve.
Prolactin levels may be falsely low on laboratory testing due to the hook effect. If the
serum PRL level is extremely high, the amount of PRL antigen may saturate the capture
antibody in the radioimmunoassay, leading to a falsely low PRL value. If a prolactinoma
is suspected, the PRL level should be tested again with serial dilutions in order to
determine the true PRL level.
There is considerable heterogeneity in circulating PRL due to posttranslational
modification. 80-90% of PRL in serum is monomeric, while 8-20% is dimeric, and 1-5%
is polymeric (41). Larger polymeric variants have decreased bioactivity. Some patients
with elevated levels of basal PRL but normal reproductive function have elevated
proportions of polymeric PRL that result in decreased PRL bioactivity (41).
Dynamic tests of PRL secretion, using TRH, hypoglycemia, chlorpromazine, or L-dopa,
provide useful information about the mechanism of control of PRL secretion but have
a limited value in the differential diagnosis of hyperprolactinemia. The patient's medical
history, physical examination, blood chemistries, thyroid function tests and pregnancy
test should be reviewed to assess for non-hypothalamic-pituitary causes.
Growth Hormone
GH is required for normal human growth; it plays little role in the first year of life, but
becomes very important during puberty. It is secreted in bursts by the somatotroph cells,
and its release is controlled by GHRH and somatostatin which stimulate and inhibit its
release, respectively. GH, in turn, stimulates the liver's production of somatomedin-C,
also known as insulin-like growth factor 1 (IGF-1). IGF-1 mediates many of the effects
of GH, including stimulating somatostatin release at the hypothalamus and inhibiting GH
release at the pituitary.
Sleep, stress, exercise and hypoglycemia increase the release of GH, while obesity,
hyperglycemia and excess glucocorticoids decrease it. GH increases the uptake of amino
acids into tissue, and an increase in amino acids increases GH release in a healthy
individual. GH and IGF-1 levels are highest in children and young adults, then decrease
with age in normal subjects. In normal subjects, serum GH levels are very low or
undetectable for most of the day. GH has a half life of 20-30 minutes and is secreted in
short pulses, with 2-7 peaks per day. Some of these bursts are associated with meals, while
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others occur during the early stages of sleep. The half life of IGF-1, on the other hand, is
2-18 hours, and serum levels are relatively stable throughout the day.
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frontal bossing, deepening of the voice, organomegaly, hyperhidrosis, acanthosis
nigricans, enlargement of the hands and feet leading to an increase in ring, glove and shoe
size, and headache. Insulin resistance can lead to diabetes mellitus. Enlargement of
the tongue can lead to sleep apnea. Excess soft issue in the hands leads to a doughy
handshake, and excess soft tissue in the feet can lead to a noticeable increase in heel-pad
thickness on radiographs. Acromegalic patients may also suffer from proximal myopathy
and weakness, osteoarthritis, carpal tunnel syndrome, cardiomegaly and hypertension.
Accelerated atherosclerosis and metabolic changes lead to a shortened life span, with death
generally from cardiovascular, cerebrovascular or respiratory events.
GH excess with acromegaly or gigantism is usually due to a GH-secreting pituitary
adenoma. The average acromegalic patient has symptoms for eight to ten years before
being diagnosed, so these tumors are generally quite large on presentation. Many of these
lesions will compress the optic apparatus and lead to a decrease in visual acuity or
bitemporal hemianopia before the tumor is recognized.
Workup
When acromegaly or gigantism are suspected, a thorough endocrine evaluation
should include measurement of basal GH and IGF-1 levels as well as testing to assess for
suppression of GH secretion with hyperglycemia. Exercise and stress can stimulate GH
production, so serum GH levels should be obtained early in the morning, before the
patient arises from bed, or 2 hours after a meal, when GH levels should be suppressed.
There is some heterogeneity in serum GH due to post-translational modification and
differential splicing (6, 13, 24). Two main forms of GH are found in the circulation; the
22K form accounts for 90% of serum GH, while the 20K form makes up 5% (24).
This heterogeneity may account for differences between radioimmunoassay values and
actual biological activity. Although GH binding proteins exist in circulation, it is unclear
whether they affect GH activity physiologically.
In healthy subjects, basal GH levels are usually <5 ng/mL while more than 90% of
acromegalic patients have levels >10 ng/mL. Levels vary widely, however, so some
acromegalic patients have normal GH levels. In acromegalic patients, the normal
pulsatile GH secretory pattern is replaced by a more consistent elevation throughout the
day (4). Due to the short half life and pulsatile secretion, random GH levels are of
limited value and single determinations of GH correlate poorly with severity of disease.
Serum GH levels may be elevated in other conditions as well, including uncontrolled
diabetes mellitus, malnutrition, renal failure, and during physical or emotional stress (11).
To confirm a diagnosis of acromegaly, a glucose suppression test can be performed.
In a normal glucose suppression test, GH will suppress to <2 ng/mL after glucose
loading, while in an acromegalic patient, this suppression will fail to occur (22).
Because serum levels of IGF-1 are more stable than those of GH, measurement of IGF1 can be used to provide a reliable indicator of the overall exposure of GH on the
body. IGF-1 is increased in nearly all patients with acromegaly, even in those whose serum
GH levels are within the range of normal. Normal levels of IGF-1 range from 0.45-2.2
U/mL in women and from 0.34-2.0 U/mL in men (11). IGF-1 is not directly affected by
stress or exercise, and it is bound to carrier proteins that regulate its function and
stabilize its levels. There are at least four different IGF-binding proteins (IGFBPs), the
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levels of two of which can be measured to assist in the diagnosis of acromegaly. The serum
level of IGFBP-1 is correlated inversely with the amount of GH, while the level of
IGFBP-3 will correlate directly with GH. IGF-1 is also a reliable parameter for posttreatment follow-up of acromegaly, since it reflects GH secretion over the prior 24
hours (25).
Additional testing may be needed to confirm the diagnosis of excessive GH production.
Thyrotropin releasing hormone (TRH) stimulation does not cause a significant change
in GH levels in normal subjects, but will lead to a 50% rise in GH in untreated
acromegalics. Though this finding also occurs in patients with liver disease, renal failure
or depression, it can be highly suggestive of acromegaly in the correct clinical setting. This
test may provide useful therapeutic information as well, as patients who have a positive
response to TRH-stimulation may respond to bromocriptine therapy. TRH-stimulation
may also be used to identify those patients who, despite a normal GH level after surgery,
have residual GH-secreting tumor and are therefore at risk of tumor recurrence (12, 36).
An L-Dopa test may also be performed. Administration of oral L-Dopa to a normal
fasting subject will stimulate GH secretion, while it will paradoxically lower GH levels in
a fasting patient with acromegaly (8). Likewise, Bromocriptine, a dopamine agonist that
binds D2 receptors, will raise GH levels in a normal subject, but lower them in
acromegalic patients. Other dynamic tests include the arginine-stimulation test,
somatostatin-stimulation test, LH-releasing hormone stimulation test, and insulininduced hypoglycemia stimulation. Each of these tests may also provide additional
information in cases of acromegaly.
As GH-producing pituitary lesions are often large at the time of diagnosis, patients
should undergo formal visual-field testing and endocrine testing for hypopituitarism, in
addition to an MRI with thin cuts through the sella.
Those rare patients who have acromegaly, but no pituitary lesion on MRI, should
undergo a workup to find another site of a GHRH-secreting tumor. GHRH levels can be
useful in this workup. Ectopic acromegaly, due to non-central nervous system causes such
as a pancreatic islet cell tumor or a bronchial carcinoid, will result in a significantly
elevated level of circulating serum GHRH, whereas GHRH is barely detectable in
acromegaly due to a pituitary lesion (5).
Hypothalamic-Pituitary-Adrenal Axis
Cortisol is necessary for the homeostatic biochemical and physiologic responses to
stress, and the hormone is essential for life. Cortisol secretion is regulated by the
hypothalamic-pituitary-adrenal (HPA) axis. Psychological and physical stress and
signals from the brain to produce the diurnal rhythm of plasma cortisol levels stimulate
the hypothalamus to secrete corticotrophin releasing factor (CRH) which then stimulates
pituitary ACTH production. ACTH is produced by the corticotrophs while they are
producing pro-opiomelanocortin. The adrenal glands then secrete cortisol in response
to ACTH. This HPA axis is regulated by the balance between stimuli that encourage
secretion of CRH and ACTH, and the negative feedback inhibition from cortisol on
production of CRH and ACTH (Figure 3).
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Both ACTH and cortisol have pulsatile secretion patterns. In a normal subject,
ACTH peaks in the early morning, then declines to a nadir around midnight (32).
Circadian rhythms affect ACTH secretion, so levels are affected by light and change in
time-zone. Physical trauma, surgery, fever, hypoglycemia and other stressors lead to an
increase in ACTH and cortisol secretion. The half life of bioactive ACTH is only 4-8
minutes, while its immunoreactive half life is quite variable.
Glucocorticoids increase gluconeogenesis and prevent glucose uptake into peripheral
tissues. With extended exposure to glucocorticoids, lipolysis is enhanced and body fat
redistribution occurs. Glucocorticoids suppress inflammatory responses, lower peripheral
lymphocyte counts and raise granulocyte counts. They lead to an increase in osteoclasts
and a decrease in osteoblasts, and thereby diminish new bone formation. Linear growth
is suppressed in children. The catabolic effects of glucocorticoids cause the destruction
of muscle proteins and lead to myopathy. Fibroblast proliferation and function are
inhibited, as are some extracellular matrix proteins, leading to impaired wound healing.
Glucocorticoids can also have psychological and behavioral effects, causing altered
mood, sleep and cognition.
Cortisol Deficiency
Adrenocortical insufficiency leads to nausea and emesis, abdominal pain, anorexia,
weight loss, generalized weakness, hypotension, hyponatremia, and the inability to
respond to stressful stimuli. Primary adrenocortical insufficiency, or Addison's disease,
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disorder (16). In primary adrenal disease, diminished cortisol production provides
decreased negative feedback inhibition on the pituitary corticotrophs, so basal ACTH
levels should be high. Conversely, in patients with pituitary disease or those with
prolonged glucocorticoid exposure, basal ACTH levels are low and are unable to
respond normally to CRH stimulation.
The insulin tolerance test (ITT) and glucagon stimulation test (GST) can be used to
determine how the HPA axis responds to stress. The ITT, as discussed earlier, is
considered by many to be the 'gold-standard' for measuring both GH and ACTH
reserves (1, 29). A bolus of insulin, 0.15 units/kg, is given IV, to induce hypoglycemia. A
normal response is a cortisol increase of 200 nmol/L, reaching a peak level of at least 500
nmol/L (32).
A glucagon-stimulation test is not as widely used as the ITT, but may be useful in those
patients for whom an ITT would be contraindicated. An IM injection of 1 mg glucagon
is given, then ACTH and GH levels are measured six times, starting at 90 minutes
post-injection and continuing every 30 minutes thereafter. Normal cortisol response is
delayed but otherwise similar to that for the ITT.
Cortisol Excess; Cushing's Syndrome
Longstanding exposure to excess cortisol leads to Cushing's syndrome. Multiple
processes can lead to this syndrome, and determining the exact cause in a particular
patient may be difficult. Generally, late evening plasma levels are elevated over the
normal values of five to 25 ng/mL and the usual diurnal variation in levels is lost,
leading to an elevated mean cortisol level. This chronic hypercortisolemia suppresses
hypothalamic CRH and pituitary ACTH secretion, and the pituitary corticotrophs
atrophy.
Approximately 75% of patients with Cushing's syndrome, endogenous adrenocortical
hyperfunction, have Cushing's disease, excess ACTH secretion from a pituitary
corticotroph tumor. Many of these ACTH-secreting adenomas are microadenomas
which may not be visible even on high quality sellar MRI. Cushing's syndrome patients
may also have an ectopic, non-pituitary, source of excess ACTH production. This is most
often due to small cell lung carcinoma, but may also be attributable to bronchial
carcinoid, thymic carcinoid, pancreatic carcinoid, pancreatic islet cell tumor,
pheochromocytoma, medullary thyroid carcinoma or another neuroendocrine tumor.
There are also rare CRH-secreting tumors, generally bronchial carcinoids. Other patients
with Cushing's syndrome have adrenal tumors that secrete cortisol rather than ACTH.
These may be benign adenomas or malignant carcinomas, and the syndrome can be
clinically indistinguishable from that of Cushing's disease or ectopic ACTH-secreting
tumors. Therefore, endocrine testing to determine the etiology of Cushing's syndrome
is very important.
Symptoms associated with Cushing's syndrome include central weight gain, often
accompanied by a buffalo hump; moon facies, due to thickening of facial fat;
hypertension; hyperglycemia or diabetes mellitus; hirsutism; acne; purple striae; facial
telangiectasias; amenorrhea or hypogonadism; muscle wasting; osteoporosis;
hyperpigmentation; and depression. Patients with Cushing's syndrome lose the normal
diurnal cortisol variation. In Cushing's disease, the HPA axis maintains its homeostatic
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responses, but is altered to respond only to higher than normal glucocorticoid levels.
Cushing's syndrome from an ectopic ACTH-secreting tumor, on the other hand, will
exhibit autonomous cortisol production and fail to demonstrate any feedback inhibition.
Cushing's disease is diagnosed if a patient has 1. increased basal cortisol levels, 2.
relative resistance to negative feedback from glucocorticoids, 3. ACTH response to
decreased cortisol, 4. ACTH response to CRH or vasopressin, 5. cortisol response to
exogenous ACTH, and 6. a pituitary source of the excess ACTH.
Workup
When Cushing's syndrome is suspected, one must first establish that there is indeed
excess secretion of cortisol. This may be accomplished via tests that 1. directly or
indirectly measure cortisol production over 24 hours, such as via 24-hour urine
collection for free cortisol and 17-hydroxyglucocorticoid excretion and 2. assess the
presence of normal sensitivity of the hypothalamic-pituitary-adrenal axis to negative
feedback by glucocorticoids, for instance, by using a low-dose glucocorticoid tests
including the overnight test or the low-dose portion of the 6-day dexamethasone
suppression test.
Serum free cortisol filters into saliva and urine, and cortisol urinary excretion
products are elevated. 24 hour urine free cortisol (UFC) is 20-90 g in a normal subject,
but increases to >150 g in Cushing's syndrome. Some of the metabolites of cortisol,
including 17-hydroxysteroids (17-OHCS), and some of its precursors, including 17ketosteroids and DHEAS, are elevated as well. The saliva and urine free cortisol levels are
more accurate indicators of increased cortisol secretion than is urinary 17-OHCS, as they
increase more rapidly after plasma cortisol exceeds the binding capacity of transcortin.
Salivary cortisol is easy to use in an outpatient setting and allows for repeated sampling.
An 11:00PM salivary free cortisol >3.6 nmol/L is highly suggestive of Cushing's
syndrome.
Once it is determined that a patient has Cushing's syndrome, then the next step is to
determine the source of the excess hormone production. The differential diagnosis
includes ACTH-dependent processes which lead to Cushing's syndrome by excess
ACTH secretion, and ACTH-independent processes which lead to the syndrome by excess
cortisol secretion. ACTH-dependent lesions include ACTH-secreting pituitary tumors,
ectopic ACTH-secreting tumors such as small cell lung carcinoma, diffuse corticotroph
hyperplasia, and ectopic CRH secretion, while ACTH-independent processes include
cortisol-secreting primary adrenal disease (Table 2).
Table 2 Etiology of Cushing's Syndrome. (Copied from Oyesiku N: Assessment of Pituitary
Function, Rengachary S, Ellenbogen R (eds): Principles of Neurosurgery. New York, Elsevier
Mosby, 2005)(30)
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Normal ACTH is <10 pg/mL (2 pmol/L). Patients with ACTH-dependent disease have
excess cortisol due to excess ACTH, so they will have plasma ACTH levels which are
inappropriately elevated for the level of cortisol present. Conversely, the hypothalamic
and pituitary portions of the HPA axis are relatively normal in primary adrenal disease,
so hypercortisolemia will suppress pituitary ACTH secretion in these patients, and
their serum ACTH levels will be undetectable or very low. A simultaneous serum
cortisol level must be drawn to properly evaluate the plasma ACTH level.
Patients in whom ACTH-independent Cushing's syndrome is suspected should
undergo MRI or CT adrenal imaging. Nearly 100% of these patients will have an
adrenal tumor, most of which can be visualized radiographically. When ACTHdependent Cushing's syndrome is suspected, the differential is a bit larger. Most ACTHsecreting pituitary and ectopic tumors are very small and are not easily recognized on
radiographic imaging. Basic endocrinologic principles can assist in making the diagnosis.
ACTH-secreting pituitary adenomas are well-differentiated tumors that originate from
pituitary corticotrophs. They are therefore more likely to respond to glucocorticoids and
to CRH stimulation than are ectopic ACTH-secreting tumors, which arise from tissues
that are not supposed to secrete ACTH, respond to glucocorticoids or contain receptors
for CRH. Therefore a dexamethasone suppression test (DST) or CRH-stimulation test
may be useful.
In the overnight DST, 0.5-1 mg of dexamethasone is given orally at midnight, and
serum cortisol is checked at 8:00AM the next morning, while in the two day low-dose
DST, 0.5 mg of dexamethasone is given orally every 6 hours for 8 doses. In normal
subjects, these doses are enough to suppress the HPA axis, leading to serum cortisol levels
<140 nmol (5 g/dl), urinary 17-OHCS <6.9 mol (2.5 mg) in 24 hours, and urinary free
cortisol <55 nmol (20 g) in 24 hours. Patients with Cushing's syndrome, on the other
hand, will not have this HPA axis suppression.
The high dose DST gives patients 2 mg dexamethasone. Patients with Cushing's
disease will generally suppress their levels to 50% of their baseline with this test, while
patients with ectopic ACTH tumors or adrenal tumors will not have any significant
suppression with either the high or low dose tests.
The CRH or AVP suppression tests can also help differentiate Cushing's disease
from ectopic lesions. CRH and AVP are physiologic secretagogues to which most
pituitary microadenomas will respond. In Cushing's disease, either compound will
lead to a significant increase in ACTH, while in cases of ectopic ACTH secretion,
ACTH levels will not respond.
The metyrapone test is a less common test that can also be used to distinguish
between a pituitary and an ectopic ACTH source. Metyrapone is a compound that
inhibits cortisol synthesis at several steps, including at the conversion of 11-deoxycortisol
to cortisol. As plasma cortisol levels fall, corticotrophs respond by increasing production
of ACTH, which can be measured via increased urinary 17-OHCS. For patients with
ectopic ACTH production, the hypothalamic and pituitary axis is chronically suppressed
and is not reactivated with metyrapone.
Another test which can help to differentiate between pituitary and non-pituitary
disease processes is the high dose 6 day dexamethasone suppression test known as the
Liddle test. In this test, a patient undergoes 2 days of baseline urinary 17-hyrdroxysteroid
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measurements, then is given 2 days of low dose dexamethasone, 0.5 mg orally every 6
hours, lastly he is given 2 days of high dose dexamethasone, 2 mg orally every 6 hours.
Liddle first observed in 1960 that the majority of patients with a pituitary source of excess
ACTH, Cushing's disease, had a more than 50% decrease in 17-OHCS excretion on the
second day of high-dose glucocorticoid administration, while this response was not seen
in patients with adrenal tumors (15).
Once Cushing's disease is suspected, the location of the tumor must be established.
When radiographic imaging does not demonstrate a lesion, inferior petrosal sinus
sampling (IPSS) can assist with this. The petrosal sinuses drain the pituitary gland.
Bilateral catheters are placed via the femoral veins and fed up the internal jugular veins
to the inferior petrosal sinuses. ACTH levels are measured in the peripheral circulation
and each sinus both before and after IV injection of CRH to stimulate ACTH secretion.
Bilateral catheterization allows for simultaneous sampling of the right and left sinuses so
that the ACTH concentrations can be compared. A gradient between the sinuses can
lateralize the tumor within the pituitary. As spontaneous ACTH release is episodic in
nature, CRH stimulation helps to ensure secretion at the time of sampling. An inferior
petrosal sinus to peripheral blood (ISP:P) ratio >2.0 in basal samples has up to 95%
sensitivity and 100% specificity, while a peak IPS:P ratio >3.0 after CRH administration
has been reported to have 100% sensitivity and 100% specificity (14, 28, 38). An intersinus gradient >1.4 predicts the location of the lesion in up to 75% of patients. Cavernous
sinus sampling is less commonly used, but can provide slightly more accurate localization
(Table 3).
Table 3 Clinical Approach to Patients with Suspected Cushing's Syndrome. (Copied from Oyesiku
N: Assessment of Pituitary Function, Rengachary S, Ellenbogen R (eds): Principles of Neurosurgery.
New York, Elsevier Mosby, 2005)(30)
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measured as part of the IPSS to assist in localizing the tumor.
Most patients undergo a combination of these tests. It is important to establish that the
patient does indeed have Cushing's syndrome before proceeding with tests to determine
if the diagnosis is Cushing's disease or an ectopic source. In subjects without Cushing's
syndrome, pituitary ACTH secretion is suppressed by dexamethasone and responds to
CRH. This can therefore be erroneously attributed to Cushing's disease, causing a
normal patient to undergo unnecessary pituitary surgery.
Glycoprotein Hormones
The glycoprotein pituitary hormones are thyroid-stimulating hormone (TSH),
follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Each of these is
composed of 2 glycopeptide chains: an alpha chain and a unique beta chain. These chains
are synthesized individually, and there is generally a slight excess of the alpha chain which
can be detected with radioimmunoassay.
Pituitary-Thyroid Axis
Hypothalamic secretion of TRH to the portal venous complex regulates the production
and secretion of thyroxine (T4) and triiodothyronine (T3). When thyrotrophs sense
TRH, they release TSH, which acts on the thyroid gland to release T3 and T4. T3 and T4,
in turn, inhibit hypothalamic TRH release and pituitary TSH release. Somatostatin,
glucocorticoids and dopamine also suppress both TRH release and the pituitary response
to TRH.
Hypothyroidism
Signs and symptoms of hypothyroidism include fatigue, dry skin, cold intolerance,
alopecia, and, in severe cases, myxedema coma. Most patients with hypothyroidism have
primary hypothyroidism due to a disorder of the thyroid gland. Autoimmune
Hashimoto's thyroiditis, thyroid destruction after 131I therapy and surgery for
hyperthyroidism are the most common causes of this condition. In primary
hypothyroidism, absence of the feedback inhibition of the thyroid hormones on the
pituitary and hypothalamus results in elevated TRH and TSH levels. When patients are
untreated, the increased TRH secretion stimulates thyrotroph hyperplasia and may
lead to pituitary enlargement. As TRH also stimulates PRL secretion, these patients may
be misdiagnosed with a PRL-secreting or TSH-secreting tumor.
TSH deficiency causes secondary hypothyroidism and results from pituitary or
hypothalamic disease. It frequently accompanies pan-pituitary deficiency from a large
pituitary adenoma or suprasellar mass.
Workup
The mean TSH concentration in euthyroid adults is 1.4-2.0 U/ml. These levels do not
differ significantly with gender or with age between adolescence and about 60 years. TSH
levels rise to a peak between midnight and the early morning and drop to a nadir in the
late afternoon (26, 31). Increased TSH levels are seen in hypothyroidism, TSH-secreting
tumors, and with some drugs, including iodine and dopamine antagonists. Decreased
TSH levels occur with hyperthyroidism, severe illnesses, chronic renal failure, pan-
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Workup
As with the evaluation of hypothyroidism, TSH levels should be measured, but they
may not provide the full picture. Patients with hyperthyroidism due to primary thyroid
disease will have elevated serum levels of free T4, with a low plasma TSH. A TRH
stimulation test may be useful in the assessment of mild thyroid dysfunction and in the
functional evaluation of the hypothalamic-pituitary-thyroid axis. Serum TSH levels
are measured at baseline and again after the administration of TRH. A dose-response
relationship between TRH and TSH levels is observed (18). In primary hyperthyroidism,
the excess thyroid hormones will inhibit the pituitary thyrotrophs, so the pituitary
TSH response to TRH stimulation will be suppressed.
Secondary hypothyroidism, from a pituitary or hypothalamic disorder, will generally
demonstrate low levels of T4 in combination with lower than expected levels of TSH.
Serum TSH levels are not always useful, however, as they may appear normal if the
patient secretes a form of TSH which is detectable on radioimmunoassay but biologically
inactive.
In TSH-secreting tumors, the production of alpha and beta subunits is imbalanced
such that excess alpha subunit is secreted, which produces a ratio of serum alpha
subunit to serum TSH of >1. In a patient with hyperthyroidism, or a patient with a
pituitary tumor who has been previously treated for hyperthyroidism, an elevated TSH
level combined with an elevated ratio of alpha-subunit to TSH, indicates a TSHsecreting pituitary adenoma.
In patients who have had ablative thyroid treatments for misdiagnosed TSH-secreting
pituitary tumors, elevated plasma TSH levels do not fully suppress when the patient is
given thyroid hormone, and the pituitary TSH response to TRH is blunted.
Gonadotropins
FSH and LH are produced and released by the gonadotrophs of the adenohypophysis
to regulate ovarian and testicular function. In women, FSH stimulates growth of the
granulosa cells of the ovarian follicle and controls their estrogen secretion. At the
midpoint of the menstrual cycle, the increasing level of estradiol stimulates a surge of LH
secretion, which then triggers ovulation. After ovulation, LH supports the formation of
the corpus luteum. Exposure of the ovary to FSH is required for expression of the LH
receptors. In men, LH is responsible for the production of testosterone by Leydig cells in
the testes. The combined effects of FSH and testosterone on the seminiferous tubule
stimulate sperm production.
FSH and LH secretion occur in a pulsatile fashion in response to pulses of secretion of
GnRH from the hypothalamus. GnRH is also known as LH-releasing hormone (LHRH)
because of its potent stimulation of LH secretion. Levels of FSH and LH are regulated by
a balance of GnRH stimulation, negative feedback regulation from the inhibin peptide
secreted by the ovaries and the testes, and the effect of the sex steroids on the pituitary and
the hypothalamus. Appropriate concentrations of FSH and LH are required for normal
sexual development and reproductive function in both women and men. LH and FSH
circulate in blood predominantly in the monomeric form found in the pituitary. FSH has
a half life of 3-5 hours, so serum levels are more stable than are those of LH, which has
a half life of 30-60 minutes.
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GnRH stimulates gonadotropin secretion from the pituitary for the first few months
of life, then the pituitary becomes unresponsive to GnRH until puberty, when pulsatile
secretion of FSH and LH occur in response to pulses of GnRH. At menopause, when
gonadal failure occurs, the negative feedback provided by the hormonal products of the
gonads is eliminated so serum levels of FSH and LH increase.
Gonadotropin Deficiency and Workup
Hypogonadism presents in women as amenorrhea and loss of libido associated with
uterine and vaginal atrophy. In men, low testosterone results in loss of libido, impotence,
decreased beard growth and body hair, and testicular softening.
When hypogonadism is suspected, endocrine evaluation should include measurement
of plasma FSH, LH and sex hormones estradiol in women and testosterone in men. FSH
and LH are measured by immunoassay. In men above the age of puberty, these levels are
within a fairly narrow range. In women, however, the pulsatile nature of LH and FSH,
and their marked fluctuation during the menstrual cycle, pregnancy and menopause have
to be considered in the interpretation of these lab results. In adolescents and women,
isolated and random FSH and LH levels are of little diagnostic use alone, and must be
correlated with the results of simultaneous levels of estradiol or testosterone and the
results of dynamic testing.
Estradiol binds to sex-hormone binding globulin which will have elevated levels in
women who are taking oral contraceptive pills or hormone replacement therapy.
Testosterone in men has a significant diurnal variation, and should be assessed between
8:00am and 9:00am.
Primary hypogonadism is associated with low levels of sex steroids and high levels of
FSH and LH. This may be due to primary ovarian failure such as with ovarian dysgenesis,
oophorectomy or premature ovarian failure, or primary testicular failure such as with
Klinefelter's syndrome or orchiectomy. Decreased levels of FSH and LH may also be
found in hypothalamic disease including tumors such as craniopharyngiomas or
hypothalamic region meningiomas, germinomas, gliomas or hamartomas, as well as other
hypothalamic infiltrative or infectious pathology such as sarcoidosis, eosinophilic
granuloma, tuberculosis, fungal infections or syphilis. Hypothalamic trauma, vascular
disease and radiation therapy can also be the cause.
If FSH and LH are inappropriately low and are associated with a decreased level of
estradiol or testosterone, then hypogonadotropic hypogonadism can be diagnosed.
This may be a primary result of congenital causes, as with Kallman's syndrome, in
which GnRH deficiency is associated with anosmia and defective development of the
midline structures of the brain. More commonly however, hypogonadotropic
hypogonadism is a secondary, acquired defect of GnRH production associated with
hypothalamic dysfunction, as occurs with destruction of the pituitary gonadotrophs or
interruption of pituitary stalk function from a sellar mass or apoplexy, or from surgery
or radiation to treat a sellar tumor, or as a result of stress, systemic disease, anorexia
nervosa or bulimia, or sometimes seen in very athletic women.
GnRH stimulation testing is rarely used today, but at times may be useful to determine
the presence of adequate gonadotroph reserve. If a detectable elevation of FSH and LH
levels occurs after GnRH administration, functional gonadotropic cells are still present.
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This response to GnRH may require priming of the gonadotrophs with repeated
injections of GnRH.
Gonadotropin Excess and Workup
Elevated FSH and LH may be seen with polycystic ovary syndrome, paraneoplastic
gonadotropin secretion, precocious puberty and gonadotrope-secreting adenomas.
Though FSH-secreting and LH-secreting pituitary adenomas are rarely observed
clinically, approximately 5% of pituitary adenomas have immunohistochemical staining
for the gonadotropins or their subunits. Nearly all of these tumors are clinically
nonfunctioning pituitary macroadenomas that cause symptoms because of their mass
effect on sellar or parasellar structures, as there is no characteristic hypersecretory
endocrinopathy, as occurs with other hormone secreting tumors. About 20% of these
tumors secrete the alpha-subunit rather than a complete gonadotropin.
Precocious puberty is often associated with hypothalamic hamartomas in children.
These tumors interrupt the normal suppression of pituitary gonadotropin function
by higher neural centers, leading to pulsatile secretion of GnRH and, in turn, secretion
of FSH and LH, estrogen, and testosterone and premature sexual development. Sustained,
non-pulsatile exposure to GnRH desensitizes the gonadotrophs to GnRH and inhibits
FSH and LH release. A long-acting analogue of GnRH is used to suppress pituitary
gonadotropin secretion and reverse sexual development in children with idiopathic
precocious puberty or precocious puberty due to a hypothalamic hamartoma. Ectopic
production of gonadotropin, usually of human chorionic gonadotropin which has LHlike activity, by germinomas, lung carcinomas and other tumors may also lead to
precocious puberty.
Posterior Pituitary Hormones
The neurohypophysis is the posterior lobe of the pituitary. This lobe secretes
antidiuretic hormone (ADH) and oxytocin, which are produced by hypothalamic
neurons but are stored in secretory granules in the nerve terminals of the
neurohypophysis and are released from there in response to various stimuli.
If the posterior pituitary is selectively damaged but the median eminence and
hypothalamus remain intact, these hormones can be secreted from the median eminence.
Antidiuretic Hormone
ADH conserves water by reducing the rate of urine output. This antidiuretic effect is
achieved by promoting the reabsorption of solute-free water in the distal collecting
tubules of the kidney. Though this hormone is also known as vasopressin, it has little to
no cardiac pressor effect in healthy humans. Through the action of ADH, serum sodium
concentrations and serum osmolality are maintained within a narrow range, despite large
daily variations in sodium intake and water loss. Derangements in ADH secretion can lead
to severe, life-threatening disturbances in serum osmolality and volume.
Though multiple hypothalamic signals influence ADH secretion, the primary stimuli
for ADH release are an increase in plasma osmolality or a decrease in plasma volume.
Even a 2% increase in plasma osmolality caused by an impermeable solute, such as NaCl,
causes shrinkage of hypothalamic osmoreceptor cells, stimulating ADH release as well as
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Higher neural centers also influence ADH levels. Beta-adrenergic and cholinergic
agonists stimulate ADH secretion, while alpha-adrenergic agonists and atropine inhibit
it. Psychological factors, pain, and stress can therefore increase ADH release. Nausea is
an instantaneous and extremely potent stimulus for ADH secretion in humans. Other
stimuli for ADH release include hypoglycemia, angiotensin, nicotine, morphine, and
barbiturates, while inhibitors of ADH release include alcohol, phenytoin, and narcotic
antagonists.
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Deficient ADH; Diabetes Insipidus
The typical clinical manifestations of diabetes insipidus (DI) include polyuria, polydipsia,
excessive thirst and nocturia. Polyuria may be defined as the excretion of more than 2.5
L of urine per 24 hours on at least 2 consecutive days, provided that patients are
allowed free access to and drink water ad libitum. The severity of diabetes insipidus varies
widely, with urine volumes ranging up to 20 L per day. If access to water is restricted,
dehydration can rapidly become severe and result in altered mentation, fever,
hypotension, and death.
Central DI is deficient ADH secretion from the neurohypophysis in response to
normal osmotic stimulation. This disorder is also known as hypothalamic DI, cranial DI
or neurogenic DI. These patients generally have normal thirst sensation though they have
insufficient circulating antidiuretic activity. Diabetes insipidus secondary to renal
tubular insensitivity to the antidiuretic effect of ADH is usually called nephrogenic
diabetes insipidus. These patients generally have a normal of high level of circulating
ADH. Primary polydipsia is a third mechanism leading to diabetes insipidus. This is the
ingestion of excessive volumes of water, resulting in suppression of vasopressin release
and consequent polyuria.
Causes of central DI include sellar and parasellar tumors, especially
craniopharyngiomas, large non-functional pituitary adenomas, germinomas, and
metastatic tumors; hypothalamic tumors or infiltrative processes such as sarcoidosis and
histiocytosis-X; pituitary or hypothalamic injury or surgery; head trauma; subarachnoid
hemorrhage from ruptured intracranial aneurysms; and idiopathic causes. DI is rarely a
presenting feature in patients with pituitary adenomas, but is more common in patients
with craniopharyngioma or hypothalamic lesions. DI from head trauma or damage to the
pituitary stalk or hypothalamus generally presents with 24 hours of injury. In about 50%
of cases of posttraumatic diabetes insipidus, the condition resolves spontaneously
within a few days. Permanent diabetes insipidus develops in another 30-40% of these
patients, and the remainder exhibit a triphasic response to injury. In this last group, the
onset of polyuria is abrupt but lasts only a few days. It is followed by a period of antidiuresis similar to SIADH that lasts 2-14 days before permanent DI develops. This
triple response to injury is believed to be attributable to release of the stored ADH
within the neurohypophysis (27, 40).
Glucocorticoid deficiency or thyroid hormone deficiency can lead to impairment of
the kidney's ability to excrete a water load and to dilute urine maximally. This impairment
of anterior pituitary function can therefore mask central DI, which becomes apparent
only when the hypopituitarism is treated.
Workup
Patients with DI will demonstrate persistent urine osmolality of less than 300
mOsm/kg H2O associated with urine specific gravity of 1.005 or less and plasma
osmolality greater than the normal 287 mOsm/kg H2O. To confirm the diagnosis,
patients are tested to document that there is inadequate release of ADH to an osmotic
stimulus. The safest and most widely used test to raise plasma osmolality is the water
deprivation test. In this test, baseline body weight, urine and plasma osmolality, and vital
signs are measured, then all oral intake is stopped. Water deprivation begins the night
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before the test in patients with mild polyuria, and early on the day of the test in patients
with severe polyuria. It is important that the test only be performed while the patient is
under constant supervision, to prevent severe dehydration. For patients with DI this test
can be dangerous. Hourly measurements of urine osmolality and weight are obtained.
Dehydration continues until either two sequential urine osmolalities vary by <30
mOsm/kg H2O, more than 3% of body weight is lost, or orthostatic hypotension and
postural tachycardia appear. Subjects then receive 5 units of aqueous vasopressin
subcutaneously and a final urine osmolality is measured 1 hour later. In normal subjects,
endogenous ADH secretion concentrates the urine and preserves normal plasma
osmolality. Thus, urine osmolality normally exceeds 500 mOsm/kg H2O and plateaus,
while plasma osmolality remains below 300 mOsm/kg H2O before vasopressin injection,
and urine osmolality rises less than 5% after injection. By contrast, in patients with central
DI, urine osmolality plateaus at 300-500 mOsm/kg H2O, plasma osmolality may exceed
300 mOsm/kg H2O, and urine osmolality rises >9% after vasopressin injection.
This test not only establishes whether or not diabetes insipidus is present, it also
distinguishes central DI from other causes of polyuria. In patients with polyuria from
renal disease or nephrogenic DI, the rise in urine osmolality with dehydration is limited
and does not increase after vasopressin administration. In patients with primary
polydipsia, water deprivation is prolonged before urine osmolality plateaus, and urine
osmolality does not increase after the injection of vasopressin.
The measurement of plasma ADH concentration under basal conditions can be
used as an adjunct to the water deprivation test, but this radioimmunoassay test is not
routinely available and is rarely affords diagnostic benefit.
Excess ADH; Syndrome of Inappropriate ADH Secretion
The syndrome of inappropriate antidiuretic hormone (SIADH) is the most common
cause of euvolemic hypo-osmolality. It is also the most prevalent cause of hypoosmolality of all etiologies encountered in current clinical practice, occurring in 30-40%
of all hypo-osmolar patients (21). SIADH results from excess ADH secretion, either from
the hypothalamus or from an ectopic source. This excess ADH stimulates excessive
retention of free water and leads to the inability to excrete dilute urine. This results in
hyponatremia and serum hypotonicity. When a patient has hyponatremia and low
serum osmolality, then continued ADH release, with the osmolality of urine higher than
that of plasma, is inappropriate.
The etiology of SIADH is diverse. Causes include ectopic production of ADH by
tumors, classically oat cell carcinoma; by lung tissue during inflammatory diseases
such as tuberculosis; excessive neuro-hypophyseal release of ADH caused by intracranial
disorders, including head trauma, subarachnoid hemorrhage, subdural hematoma,
pituitary apoplexy, pituitary stalk damage, intracranial surgery, encephalitis, meningitis,
intracranial abscess, or hydrocephalus; Guillain-Barr syndrome; delirium tremens;
acute psychosis; or by drugs that stimulate ADH release such as chlorpropamide,
carbamazepine or tricyclic antidepressants (20, 21).
The clinical features of SIADH include weight gain, weakness, lethargy, and mental
confusion. As serum sodium drops below 120 mEq/L seizures and coma can occur.
Hypo-osmolality is associated with a broad spectrum of neurologic manifestations. In the
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most severe cases, death can result from respiratory arrest after tentorial cerebral
herniation and brainstem compression. This process has been termed hyponatremic
encephalopathy and primarily reflects brain edema resulting from osmotic water shifts
into the brain due to decreased plasma osmolality (3, 17). Significant symptoms
generally do not occur until plasma sodium concentration falls below 123 mEq/L, and
the severity of symptoms can be roughly correlated with the degree of hypo-osmolality
(3).
The period over which hypo-osmolality develops also greatly affects the severity of
symptoms. Rapid development of hypo-osmolality will cause marked neurologic
symptoms, whereas gradual development over several days or weeks often presents
with only mild symptomatology despite profound degrees of hypo-osmolality. If given
sufficient time, the brain can counteract osmotic swelling by excreting intracellular
solutes such as potassium and organic osmolytes, an adaptive process known as volume
regulation (17, 39). Rapid development of hypo-osmolality may cause brain edema before
this adaptation can occur.
Underlying neurologic disease also affects the level of hypo-osmolality at which CNS
symptoms appear. Moderate hypo-osmolality that would be of little concern in an
otherwise healthy patient can cause morbidity in a patient with an underlying seizure
disorder. Non-neurologic metabolic disorders such as hypoxia, hypercapnia, acidosis and
hypercalcemia, can similarly affect the level of serum osmolality at which CNS symptoms
occur.
Workup
Laboratory findings in SIADH include hyponatremia, serum hypotonicity, urine
osmolality that exceeds that of plasma, and elevated urinary sodium concentration.
Plasma osmolality is generally >275 mOsm/kg H2O, urine osmolality is >100 mOsm/kg
H2O with normal renal function, and urine sodium will generally be greater than or equal
to 20 mEq/L, though this may be lower in patients who are chronically sodium depleted
of sodium. The SIADH patient will be euvolemic, without clinical signs of hypovolemia
such as orthostatic hypotension or tachycardia, or signs of hypervolemia such as ascites.
The diagnosis of SIADH is made when these features are present and after adrenal,
thyroid, renal, and hepatic dysfunction and diuretic use have been excluded.
Measurement of a plasma ADH level that is inappropriately elevated relative to
plasma osmolality confirms, but is not essential for, the diagnosis. An abnormal water
load test can also confirm SIADH. A patient is given a 20 ml/kg water bolus and
excretion and urine osmolality are measured. Inability to excrete at least 90% of the water
load within 4 hours and/or failure to dilute urine osmolality to <100 mOsm/hg H2O
demonstrate an abnormal test.
Once true hypo-osmolality is verified, the patient's extra-cellular fluid volume status
should be assessed by careful clinical examination. If the patient has SIADH and is truly
euvolemic, then he will experience no significant correction of osmolality with volume
expansion but will have improvement after fluid restriction. If fluid retention is present,
the treatment of the underlying disease should take precedence over the correction of
plasma osmolality. If hypovolemia is present, the patient must be considered to have
depletion-induced hypo-osmolality, in which case volume repletion with isotonic saline
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at a rate appropriate for the estimated volume depletion should be immediately initiated.
If diuretics have been used, the isotonic saline should be supplemented with 30-40
mEq/L potassium even if serum potassium concentrations are normal, because of the high
incidence of total body potassium depletion in these patients.
Oxytocin
Oxytocin stimulates uterine contractions at parturition and facilitates nursing through
stimulating contraction of the myoepithelial cells in the lactating mammary gland; it
works to expel milk from the secretory tissue of the breast to the nipple during suckling.
There is no significant clinical hypo- or hypersecretory syndrome, and oxytocin is not
routinely assayed in the assessment of pituitary function.
Non-endocrine Studies
In addition to the multiple endocrine studies discussed above, any patient with
suspected pituitary disease should be evaluated for ophthalmologic dysfunction as well.
Because of the proximity of the optic structures to the pituitary gland, full visual fields
should be documented and any injury to the optic nerves should be assessed. Magnetic
resonance imaging (MRI) with gadolinium should also be obtained with thin cuts
through the sella in order to evaluate for any pituitary mass or other lesion. The
assistance of the neuro-ophthalmology and neuro-radiology services in addition to
the endocrinology service will be invaluable in the assessment of these patients.
In a Nutshell
The pituitary secretes 8 peptide hormones: 6 from the anterior lobe and 2 from the
posterior lobe.
A PRL level of <2 ng/mL is associated with severe hypopituitarism; a PRL level of
>200 ng/mL is nearly diagnostic of prolactinoma.
The insulin tolerance test is the gold-standard for the biochemical diagnosis of GH
deficiency; IGF-1 levels are more accurate that GH levels in the diagnosis of
acromegaly.
For a diagnosis of Cushing's disease, a patient must have an increased basal
cortisol level, resistance to negative feedback from glucocorticoids, ACTH
response to decreased cortisol or to CRH, cortisol response to exogenous ACTH,
and a pituitary source of the excess ACTH.
SIADH causes euvolemic hypo-osmolality, while DI leads to low urine osmolality
with an elevated plasma osmolality.
Multiple Choice Questions
1. In acromegalic patients:
a. random GH levels are the easiest and most accurate diagnostic test.
b. a glucose suppression test will not suppress GH to <2ng/mL as it will in normal
subjects.
c. basal GH levels are usually 2-8ng/mL.
d. due to its short half life, pulsatile secretion and widely variable daily levels, random
IGF-1 levels are not an accurate indicator of overall GH levels.
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2. A TRH stimulation test (200-500 g IV TRH):
a. will lead to a 3-5 fold increase in PRL level in normal subjects, and can help
differentiate between primary and secondary hypothyroidism.
b. does not provide any information for prolactin level workup, but will lead to a rapid
decrease in TSH levels in normal subjects.
c. will lead to a rapid 2-6 fold decrease in PRL in normal subjects, but has no role to
play in a hypothyroid workup.
d. will lead to a less than 2-fold increase in PRL in normal subjects, and a rapid
increase in TSH levels in secondary hypothyroid patients.
3. Which is false regarding DI?
a. Typical symptoms of DI include polyuria, polydipsia, excessive thirst and nocturia.
b. Patients with DI have urine osmolality <300 mOsm/kg H2O, urine specific gravity
<1.005 and plasma osmolality >287 mOsm/kg H2O.
c. The water deprivation test is the safest and easiest test to diagnose DI as it can be
given to the patient to complete on his own and does not require medical
supervision.
d. In central DI, there is deficient ADH secretion in response to normal osmotic
stimulation; these patients often have normal thirst but insufficient circulating
antidiuretic activity.
4. Signs of SIADH include:
a. low serum sodium, high serum tonicity, low urine osmolality, low urine sodium and
tachycardia.
b. high serum sodium, high serum tonicity, low urine osmolality, low urine sodium
and bradycardia.
c. low serum sodium, low serum tonicity, high urine osmolality, high urine sodium
and euvolemia.
d. high serum sodium, low serum tonicity, high urine osmolality, high urine sodium
and orthostatic hypotension.
Answers
1. B
2. A
3. C
4. C
REFERENCES
1. [No authors listed] Testing anterior pituitary function. Lancet 1:839-841, 1986.
2. Consensus Statement. Consensus guidelines for the diagnosis and treatment of adults
with growth hormone deficiency: Summary statement of the Growth Hormone Research
Society Workshop on adult growth hormone deficiency. Journal of Clinical Endocrinology
and Metabolism 83:379-381, 1998.
3. Arieff A, Llach F, Massry S: Neurological manifestations and morbidity of hyponatremia:
correlation with brain water and electrolytes. Medicine (Baltimore) 55:121, 1976.
4. Barkan A: Acromegaly. Endocrinol Metab Clin North Am 18:277-310, 1989.
5. Barkan A, Shenker Y, Grekin R: Acromegaly due to ectopic growth hormone (GH)releasing hormone production: Dynamic studies of GH and ectopic GHRH secretion. J
Clin Endocrinol Metab 63:1057-1064, 1986.
6. Baumann G: Growth hormone heterogeneity: Genes, isohormones, variants and binding
219
379
220 Neuro-oncology
380
Suprasellar region
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
Petrosal sinus sampling with and without corticotropin- releasing hormone for the
differential diagnosis of Cushing's syndrome. N Engl J Med 325:897-905, 1991.
Orme S, Peacey S, Barth J, Belchetz P: Comparison of tests of stress-released cortisol
secretion in pituitary disease. Clin Endocrinol (Oxf) 45:135-140, 1996.
Oyesiku N: Assessment of Pituitary Function, in Rengachary S, Ellenbogen R (eds):
Principles of Neurosurgery. New York, Elsevier Mosby, 2005, pp 559-591.
Parker D, Rossman L, Pakary A, et al: Effect of 64-hour sleep deprivation on the
circadian waveform of thyrotropin (TSH); further evidence of sleep-related inhibition
of TSH release. J Clin Endocrinol Metab 64:157-161, 1987.
Pereira O, Bevan J: Preoperative assessment for pituitary surgery. Pituitary Mar 13
[Epub ahead of print], 2008.
Plotz C, Knowlton A, Ragan C: The natural history of Cushing's syndrome. Am J Med
13:597-614, 1952.
Post: Functioning Pituitary Tumors, in Rengachary S, Ellenbogen R (eds): Principles of
Neurosurgery. New York, Elsevier Mosby, 2005, pp 603-620.
Rigg LA, Lein A, Yen SS: Pattern of increase in circulating prolactin levels during
human gestation. Am J Obstet Gynecol 129:454-456, 1977.
Samaan N, Leavens M, Jesse R: Serum growth hormone and prolactin response to
thyrotropin-releasing hormone in patients with acromegaly before and after surgery. J
Clin Endocrinol Metab 38:957-963, 1974.
Sassin J, Frantz A, Weitzman E, S. K: Human prolactin: 24-hour pattern with increased
release during sleep. Science 177:1205-1207., 1972.
Swearingen B, Katznelson L, Miller K, Grinspoon S, Waltman A, Dorer DJ, Klibanski A,
Biller BMK: Diagnostic Errors after Inferior Petrosal Sinus Sampling. The Journal of
Clinical Endocrinology & Metabolism 89:3752-3763 2004.
Verbalis J, Gullans S: Hyponatremia causes large sustained reductions in brain content
of multiple organic osmolytes in rats. Brain Res 567:274, 1991.
Verbalis J, Robinson A, Moses A: Postoperative and post-traumatic diabetes insipidus,
in Czernichow P, Robinson A (eds): Diabetes insipidus in man Frontiers of hormone
research, Basel: S Karger, AG, 1985, p 247.
Whitaker M, Klee G, Kao P, et al: Demonstration of biological activity of prolactin
molecular weight variants in human sera. J Clin Endocrinol Metab 58:826, 1983.
Yamaji T, Ishibashi M, Teramoto A, et al: Hyperprolactinemia in Cushing's disease and
Nelson's syndrome. J Clin Endocrinol Metab 58:790-795, 1984.
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INTRODUCTION
Surgery remains the treatment of choice for most pituitary tumors. Of the available
surgical options, the transsphenoidal route is the dominant surgical approach. In
general, therapy for pituitary tumors should be directed at the following goals:
1. Reversing endocrinopathy and restoring normal pituitary function
2. Eliminating a mass effect and restoring normal neurological function
3. Eliminating or minimizing the possibility of tumor recurrence
4. Obtaining a definitive histologic diagnosis
Surgical Indications
Surgery is considered first-line treatment in all symptomatic pituitary tumors except
prolactinomas; in patients with prolactin secreting adenomas, surgery may be required
in the event of intolerance to, or hyporesponsiveness to, medical therapy. Surgery
should ordinarily be performed urgently in the setting of pituitary apoplexy with
compressive symptoms. Another clear surgical indication is progressive mass effect
from a large macroadenoma. These patients should always have a serum prolactin
(PRL) determination, with appropriate dilution, because prompt and dramatic shrinkage
of prolactinomas can occur with appropriate pharmacologic management. An additional
indication for surgery is the need to establish a tissue diagnosis.
Choice of Surgical Approach
The choice of surgical approach depends on several factors. The most important of
these includes the size of the sella, the size and pneumatization of the sphenoid sinus, the
position and tortuosity of the carotid arteries, the presence and direction of any
intracranial tumor extensions, whether any uncertainty exists about the pathology of the
lesion, and whether prior therapy has been administered. Craniotomy may be preferred
if the tumor has significant anterior or middle fossa extension or if a tumor with
suprasellar extension is suspected to be of sufficiently fibrous consistency so as to
prevent descent of the lesion inferiorly through the diaphragm.
Below, we review the surgical approaches for pituitary tumors, with specific emphasis on
transsphenoidal approaches. The approach is divided into phases, with key anatomical
points highlighted.
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TRANSSPHENOIDAL APPROACHES
Major considerations in the approach to the sella through the sphenoid sinus include
entry through the nostril directly (endonasal) or through the nasal cavity via a midline
incision under the lip (sublabial) and whether the microscope and/or endoscope is
used. In our practice, the endonasal endoscopic approach has become our standard
approach.
POSITIONING
Positioning is detailed in Figure 11. Briefly, the patients head is supported by a
Mayfield headrest with a horseshoe unless image guidance requiring rigid fixation is
employed. A semirecumbent position is used with the patients back at a 20 degree angle
from the horizontal, with the head above the heart (Figure 1). This facilitates venous
drainage and decreases venous pressure within the cavernous sinuses. The right shoulder
is placed at the upper right hand corner of the bed and the patients left ear is tilted toward
the left shoulder. The head may is gently turned to the right.
Fig. 1 Patient positioning and surgical team. 1, the patients right shoulder is positioned in the top righthand corner of the operative table. 2, the headrest frame is positioned to the far left. 3, the horseshoe
headrest is rotated so that the patients head is oriented toward the surgeon. 4 and 5, the patients head
is oriented at a right angle to the walls of the room to facilitate lateral intraoperative videofluoroscopy
on the draped patient. 6, the head is positioned so that the trajectory is toward the sella. This is most
easily accomplished by positioning the neck such that the dorsum of the nose is parallel with the floor.
7, the beach-chair position is used with the table angled approximately 20 degrees. 8, the patients right
hand is carefully positioned in an unobtrusive manner under the buttocks. SGN, surgeon; ASST,
assistant.
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PRE-OPERATIVE PHASE
We give prophylactic preoperative and intraoperative antibiotics and administer
corticosteroids only in patients who are adrenally insufficient on pre-operative testing.
Other patients are monitored for clinical symptoms of adrenal insufficiency and
morning serum cortisol levels are drawn on each postoperative day. Levels less than 8
ug/dl are considered low and are replaced accordingly. We give Oxymetalazone
intranasally then place cocaine-soaked patties in both nostrils to reduce nasal congestion;
these are removed before draping.
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Fig. 3 Sublabial approach. A and B, anterior and lateral conceptualization of trajectory to sella
turcica. C, nasal speculum inserted.
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exposed and two inferior nasal tunnels are created by dissecting the mucosa away from
the superior surface of the hard palate. A right anterior tunnel is created, and connected
with the right inferior tunnels, and the entire right side of the nasal septum is exposed
back to the perpendicular plate of the ethmoid. The cartilaginous portion of the nasal
septum is dislocated and reflected to the left, and a left posterior mucosal tunnel is
developed along the left side of the bony septum. After the retractor is in place, the vomer
is visualized.
Endoscopic Approaches
These approaches use straight and angled endoscopes as the sole visualization tools (i.e.,
pure endoscopic approach) or as a supplement to the operating microscope (i.e.,
endoscopic-assisted microscopic approach). Several endoscopic approaches to the sella
are used 4-7. The iterations include mono- or bi-narial techniques, two-handed approaches
with or without the endoscope holder, or three-handed or four-handed approaches
without the holder. Our bias is to perform a three-handed binarial technique with a
partial posterior septectomy without routine middle turbinectomy.
The 0 degree endoscope is used for the majority of the exposure and tumor resection.
The endoscope is brought within the nostril and the sinonasal anatomy is identified
including the nasal floor and both the inferior and middle turbinates. The middle
turbinate is lateralized and the choana and the spheno-ethmoid recess are identified. The
sphenoid ostium is then identified posterior to the inferior third of the superior
turbinate (Figure 4A); it is located about 1.5cm above the choana. Once identified,
the posterior septum can be incised and reflected contralaterally to identify the
contralateral sphenoid ostium (Figure 4B). The bone between the two ostia is then
removed providing the initial sphenoidotomy. A posterior septectomy is then completed
with care to not remove septum more anterior than the anterior limit of the middle
turbinate.
Fig. 4 A. Endoscopic view of the right sphenoid ostium (SO). The sphenoid ostium (arrow) can be
found at the inferior third portion of the superior turbinate (ST) and provides an important landmark
for the level of the sphenoid sinus. SER = sphenoethmoid recess. B. Endoscopic view following the
posterior septectomy but prior to the anterior sphenoidotomy. Both sphenoid ostia (arrows) are
visible with the endoscope in the right nasal cavity. An instrument placed through the left nostril can
be seen above both ostia. SR = sphenoid rostrum. C. After the anterior sphenoidotomy, evident the
panoramic view of the sphenoid anatomy with the optic and carotid protuberances (OP, CP
respectively), opticocarotid recess (OCR, arrow), clivus (Cl), planum sphenoidale (PS), and sellar
impression. SF = sellar floor.
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SPHENOIDOTOMY
Essential Surgical Anatomy:
Carefully study sphenoid sinus septations: not uncommonly, septations lead
directly to a carotid artery
Identify the tuberculum above and the clivus below
In the endoscopic approach, look for the carotid protuberances on each side and
the optico-carotid recesses superiorly
Microscopic
Once the anterior face of the sphenoid sinus is reached, videofluoroscopy or
neuronavigational image guidance is used to make any necessary adjustments to the final
position and trajectory of the retractor blades. Midline orientation is crucial at this stage.
With the sphenoid retractor in position, the keel of the vomer and the face of the
sphenoid are seen. On either side of the central ridge, the ostia of the sphenoid sinuses
can be identified. After the operating microscope is introduced, the anterior wall of the
sphenoid is opened. Once within the sphenoid sinus, the exposure is widened with a
right-angled punch. The mucosa within the sinus is usually resected with a cup forceps.
Resection of the mucosa aids in reducing bleeding and decreases the risk of postoperative
mucocele formation. With all internal bony landmarks clearly visible, the surgeon
reorients himself or herself with respect to the position of the carotid arteries, sellar floor,
anterior fossa floor, and clivus, correlating the operative anatomy with the imaging studies
and navigational adjuncts, ensuring that the appropriate midline trajectory is maintained.
Endoscopic
Once the initial sphenoidotomy has been performed the intersphenoid sinus septae
should be removed so that the sella can be identified. The inferior extent of the
sphenoidotomy should allow a suction to be placed on the clivus below the level of the
tumor. The proximal vomer should be protected as a reference point for the anatomical
midline. Care must also be taken to not injure the posterior nasal branches of the
sphenopalatine artery at the inferolateral margins of the sphenoidotomy. The superior
extent of the sphenoidotomy provides room for the endoscope during the tumor
resection. The sphenoidotomy should continue superiorly until the tuberculum sellae,
lateral optico-carotid recesses and planum sphenoidale are readily observed (Figure 4C).
SELLAR ENTRY
Essential Surgical Anatomy:
Carefully study the position and tortuosity of the carotids
Bluish discoloration may mark the cavernous sinuses laterally and intercavernous
sinuses above and below
A small vessel on the surface of the dura often marks midline
The sellar floor should be clearly visible in both the microscopic and endoscopic
approaches (Figure 4C). The floor varies in thickness and is opened with a blunt hook if
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thinned or with a chisel, punch if a midline septum can be grasped, or drill if excessively
thick. Care should be taken in cases of recurrence as scarring or bone ingrowth may
obscure the normal appearance of the sellar floor. In microscopic cases, the surgeon
should use careful videofluoroscopic control or image guidance to continually monitor
sellar entry, exposure, and trajectory. The panoramic endoscopic views generally provide
adequate information regarding the anatomical midline and trajectory.
An adequate bony exposure is crucial to the success of the transsphenoidal approach,
particularly when dealing with large tumors. For recurrent tumors in particular, a wide
bony opening can allow virgin dura to be uncovered. We favor a wide removal of the
sellar floor in virtually every case extending from one cavernous sinus to the other. A
small, bony margin of the sellar floor should be left, because this facilitates sellar
reconstruction at the end of the procedure.
The dura is exposed as widely as is feasible, and careful attention is paid to its appearance.
Transverse, blue intracavernous sinuses traversing the sella at the top and bottom of the
anterior dura are common. The anterior dura may appear blue and very thin, indicating
the possible presence of a cyst or an empty sella. After the dura is exposed completely, it
should be opened with great care. Before the dural incision is made, it is prudent to use
Doppler ultrasound and to review the imaging studies to assess the position of the
carotid arteries so that they are not injured by the durotomy.
The site of dural opening is then selected and incised in a cruciate or X-shaped fashion
or with the excision of a rectangular dural window. Next, an attempt is made to
establish a definite subdural cleavage plane between the pituitary gland or tumor and the
underlying dura with a blunt hook.
TUMOR REMOVAL
Essential Surgical Anatomy:
The carotids are on either side
The diaphragma should descend as the intrasellar tumor contents are extirpated
Normal pituitary gland is usually firm and yellow/orange in color
For the typical macroadenoma, the tumor is entered with a ring curet; tissue is
loosened and then removed with a relatively blunt curet and forceps. Regardless of
whether microscopic or endoscopic surgery is performed, the surgeon should attempt
tumor removal in an orderly fashion (Figure 6C). We first remove tumor in the inferior
aspect and then proceed laterally, from inferior to superior aspects on both sides,
removing tumor along the medial aspect of the cavernous sinus. The main distinction
during endoscopic removal is the ability to directly visualize tumor removal from the
cavernous sinus walls and suprasellar space (Figure 5). The surgeon must resist coring out
the central and most accessible portion of the tumor first, because this may cause
premature descent of the diaphragma and entrapment of more laterally situated tumor.
It is also important to delay the superior dissection until the lesion is relatively free
elsewhere, because this minimizes trauma to the pituitary stalk and secondarily
transmitted trauma to the hypothalamus. The diaphragma subsequently prolapses and
generally signifies that the resection is complete. When spontaneous prolapse of the tumor
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Fig. 5 Intrasellar endoscopic views. Using the endoscope, the resection cavity can be fully
inspected. A: View using the 30 endoscope looking toward the right cavernous sinus wall.
The redundant diaphragma sellae (D) obstructs the full view. B: Still using the 30
endoscope with the same vantage point, the diaphragma is elevated, which exposes
residual tumor (asterisk). C: View after the tumor residual has been removed. Note the
compressed pituitary gland against the diaphragm. D: Endoscopic view of the left
cavernous sinus wall and a portion of the sellar floor using the 30 endoscope after tumor
resection. The cavernous sinus wall appears to be intact and free of tumor residue.
CSD = cavernous sinus dura; SFD = sellar floor dura.
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Fig. 6 Schematic showing the steps of tumor resection. A, dural incision. B, subdural plane developed.
C, sequential removal of tumor inferiorly, laterally, then superiorly. D, reconstruction of sella with fat
or gelfoam pieces buttressed by a bioabsorbable plate.
the gland is deep enough, lateral pressure with a Hardy dissector usually causes the
microadenoma to herniate into the operative field. Its location can therefore be
delineated, its cavity entered, and its removal completed by use of a small ring curet and
cup forceps. In some cases a pseudocapsule is present and can be dissected free with a
satisfying feeling of total tumor removal. All surrounding suspicious tissue is removed,
and a biopsy specimen is occasionally obtained from the residual and presumably
normal pituitary gland.
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reaction), and rolled in hemostatic collagen powder. The fat is packed into the sellar cavity
to occlude the sella, to prevent spinal fluid leak, and to achieve hemostasis. The sellar floor
is then reconstructed (Figure 6). One can use bone or cartilage from the initial operative
phase or artificial constructs such as bioabsorbable plates. The reconstructive graft is
placed epidurally if a CSF leak was present and otherwise is placed intradurally.
One carefully suctions blood and surgical debris from the sphenoid cavity and the
nasopharynx prior to closure. We place Merocel nasal packs in the few patients who have
undergone submucosal dissection or in whom hemostasis was challenging. The
oropharynx is carefully suctioned prior to extubation of the patient.
Post-operative care
Vigilant postoperative monitoring of water and electrolyte balance is mandatory. Postoperative fluid loss must be distinguished from true diabetes insipidus, which is
accompanied by a brisk diuresis, defined by characteristic alterations in the serum
sodium and serum or urine osmolalities and for which prompt fluid replacement and
vasopressin are crucial. When it does occur, diabetes insipidus is usually temporary.
Patients without preoperative evidence of hypothalamic-pituitary-adrenal axis deficits
are not given exogenous steroids. Instead, they are monitored for signs of cortisol
deficiency and morning serum cortisol levels are drawn on each postoperative day.
Levels less than 8 ug/dl are considered low and patients are then given physiologic
steroid replacement. Prophylactic antibiotics are continued until the nasal packing is
removed, usually on the first or second postoperative day. The first follow-up visit
occurs about 8 weeks after surgery, at which time endocrine testing is performed and
endocrine replacement therapy administered for any deficiencies identified.
Outcomes
A summary of results of transsphenoidal surgery in a large series of pituitary adenomas
is provided in Table 1.
Cushingpicture
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Table 1 Postoperative remission and recurrence after transsphenoidal surgery for pituitary adenomas
Table 2 Complications of transsphenoidal surgery based on the senior authors experience (ERL)
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Complications
Complications from a series of over 2500 transsphenoidal cases are listed (Table 2).
Transient diabetes insipidus occurs in 18% of cases, with 2% requiring long-term
treatment8. Patients with post-operative CSF leaks are usually taken back promptly to
the operating room for exploration, repacking, and reconstruction of the sellar floor.
Iatrogenic injury to the internal carotid artery historically occurred in 1-2% of cases9,
10
, and is less common currently thanks to endoscopic visualization. Should the carotid
be injured during surgery, options include direct repair and non-obliterative packing.
Immediate angiography should be performed to delineate possible cavernous-carotid
fistula or pseudoaneurysm and a balloon occlusion test performed should the carotid
require sacrifice, usually with coiling. If the angiogram appears to be normal, it should
be repeated in one week, as late pseudoaneurysms may develop.
SUMMARY
The transsphenoidal approach is used in over 95% of cases of pituitary lesions, with
craniotomies only rarely performed for these tumors; substantial surgical series have
shown the transsphenoidal variations to be remarkably safe and effective11. The increasing
prevalence of the endoscope in transsphenoidal surgery will only enhance the safety and
versatility of this skull base approach.
REFERENCES
1. Jane JA, Jr., Thapar K, Kaptain GJ, Maartens N, Laws ER, Jr. Pituitary surgery:
transsphenoidal approach. Neurosurgery 2002;51(2):435-42; discussion 442-4.
2. Wilson WR, Laws ER, Jr. Transnasal septal displacement approach for secondary
transsphenoidal pituitary surgery. Laryngoscope 1992;102(8):951-3.
3. Zada G, Kelly DF, Cohan P, Wang C, Swerdloff R. Endonasal transsphenoidal approach
for pituitary adenomas and other sellar lesions: an assessment of efficacy, safety, and
patient impressions. J Neurosurg 2003;98(2):350-8.
4. Jho HD, Carrau RL. Endoscopic endonasal transsphenoidal surgery: experience with 50
patients. J Neurosurg 1997;87(1):44-51.
5. Jho HD. Endoscopic pituitary surgery. Pituitary 1999;2(2):139-54.
6. Heilman CB, Shucart WA, Rebeiz EE. Endoscopic sphenoidotomy approach to the
sella. Neurosurgery 1997;41(3):602-7.
7. Sethi DS, Pillay PK. Endoscopic management of lesions of the sella turcica. J Laryngol Otol
1995;109(10):956-62.
8. Nemergut EC, Zuo Z, Jane JA, Jr., Laws ER, Jr. Predictors of diabetes insipidus after
transsphenoidal surgery: a review of 881 patients. J Neurosurg 2005;103(3):448-54.
9. Laws ER, Jr. Vascular complications of transsphenoidal surgery. Pituitary 1999;2(2):16370.
10. Ciric I, Ragin A, Baumgartner C, Pierce D. Complications of transsphenoidal surgery:
results of a national survey, review of the literature, and personal experience. Neurosurgery
1997;40(2):225-36; discussion 236-7.
11. Jane JA, Jr., Laws ER, Jr. The surgical management of pituitary adenomas in a series of
3,093 patients. J Am Coll Surg 2001;193(6):651-9.
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Introduction:
The transsphenoidal approach to the pituitary was first performed by Schloffler in
Vienna in 1907. (3) The sublabial, transseptal version of this approach was initially
popularized by Cushing (4), who abandoned the approach for a transscranial approach
to pituitary lesions. Gerard Guiot in Paris continued to perform the transsphenoidal
approach he had learned from Cushing, and taught it to Canadian Jules Hardy. The
sublabial approach was then re-introduced to North America by Jules Hardy (5).
Widespread and permanent adoption of the technique is credited to Laws, Wilson,
and many others. By the 1970s, a sublabial approach to the sellar floor was generally
employed for moderate-sized lesions of the region.
During the 1990s, several teams built upon the ideas of endoscopic pituitary surgery
initially advanced by Guiot and Apuzzo (3). The use of the endoscope in transsphenoidal
surgery gained momentum due to advances in optical technology and widespread
adoption for sinus surgery by otolaryngologists. Jho (5), Cappabianca (1), and others
advanced the concept of employing endoscopes to facilitate the transsphenoidal approach
to the sellar floor. Several advantages were proposed. These included: minimal dissection
with elimination of the need for a sublabial incision, panoramic view of the central skull
base anatomy, with greater control of important structures, including carotid arteries and
optic nerves, and improved patient comfort by eliminating the need for packing.
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Disadvantages included: loss of the depth perception and hands-free visualization
provided by a binocular microscope, and the potentially problematic paramedian,
rather than midline, approach provided by a completely endonasal route.
From 1996-1997, we performed all transsphenoidal surgery done via the traditional
sublabial microscopic route, but added the use of the rigid 4mm, 18 cm sinus endoscope,
and appropriate 0-degree, 30-degree and 70-degree lenses. This was done in conjunction
with applied cadaver dissection of sinus anatomy. The advantages provided by adjunctive
use of endoscope and microscope led us in 1998 to begin using a totally endoscopic
endonasal approach to the sella. A combination of endoscopic and microscopic removal
of the sellar and parasellar pathology has proven to be effective and safe. We report our
10- year experience with the endoscopic endonasal approach.
Table 1 Sellar Pathology
Surgical Procedure
Operating Room Organization and Patient Position:
The patient is placed supine in a Mayfield headrest, with neck extended and head
turned slightly to the right. The endoscopic equipment, including monitor, light source,
video camera and recorder, are positioned above and behind the patients left shoulder.
The frameless image guidance monitor is positioned alongside. Fluoroscopic visualization
is helpful if frameless stereotaxy is not available. The surgeon stands at the patients right
shoulder; the anesthesiologist and his or her equipment are on the patients left side. The
nurse is at the patients head, with Mayo stand extending over patients left shoulder. A
microscope is positioned close but out of the way, above the patients face.
The patients face and periumbilical region are prepped and draped. The nasal
cavities are prepped with gauze pledgets of 5% chlorhexidine gluconate. Two cottonoids
soaked in xylometazoline hydrochloride are gently and temporarily placed in each nare
as nasal decongestants. The middle turbinate and septum are injected with diluted
adrenaline (1:200,000). One dose of perioperative steroids is given to all but those
patients with Cushings disease. Broad spectrum antibiotics are given pre- and 24 hours
post-operatively.
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epidural plane. An intact sellar floor is opened with a microdrill or osteotome. The
epidural dissection is performed and complete removal of the sellar floor is achieved.
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systolic blood pressure to approximately 30mmHg above the patients normal pressure.
This assures that hemostasis will remain secure with any post-operative coughing or
straining that may occur.
Sellar Reconstruction
Because the approach is a minimally invasive technique, there is generally not a
large fragment of bone or cartilage to use for sellar reconstruction. A piece of autologous
adipose is generally harvested from the umbilicus. This small incision is more cosmetically
acceptable and less painful than either the lower quadrant abdominal incision or a
lateral thigh incision. A small adipose graft is placed at the sellar floor and held in
place with fibrin sealant. In the case of an intraoperative CSF leak, the adipose is placed
within the intradural space to prevent future leakage. This is held in place with fibrin
sealant and a lumbar drained is placed post-operatively for 48 hours.
Irrigation and final hemostasis of the nasal mucosa is performed. The medial turbinate
and nasal septum are medialized (Fig. 4). No nasal packing is used. A small triangular
nasal drip pad is employed until drainage is minimal.
Material:
From 1998 to 2008, 600 patients were operated upon via an endoscopic approach to
the sphenoid sinus and sella turcica. The pathologies represented are listed in Table 1.
There were 264 non-functional adenomas (44%) and 192 prolactinomas (32%). Seventytwo patients (12%) had acromegaly, 30 patients (5%) had Cushings Disease and 42 (5%)
had other pathologies, including chordomas, encephaloceles, Rathkes Cleft Cysts, etc.
The microscope was introduced for sellar tumor removal and the 30 degree endoscope
used to remove suprasellar tumor and to examine for occult cerebrospinal fluid leaks.
Length of stay was 2-3 days, decreasing toward the end of the study period.
Results:
The patient follow-up schedule is listed in Table 2.
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Table 2 Post-Operative Transsphenoidal Surgery
Surveillance Schedule
The results of symptom control are listed in Table 3. Of 502 patients who presented
with headache, all reported their headache was improved by 3 months after surgery.
Among the 350 patients who presented with visual complaints and/or field defects,
vision was preserved or improved in 344 (98%) and worse in 6 (2%).
Control of endocrinopathy with surgery alone was considerably more difficult.
Results are listed in Table 4. Among 192 patients with prolactinomas, 120 (63%)
experienced normalized prolactin levels and were normal, without need for dopamine
agonist therapy, at most recent follow-up. For the 72 acromegalic patients, surgery
was curative in 40 patients (56%) at most recent follow-up. The remaining patients were
normalized with adjunctive radiosurgery. Three require ongoing additional suppressive
Table 3 Results-Symptom Relief
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medical therapy. Among the 30 patients with Cushings Disease, 20 (67%) were normal
at last evaluation with surgery alone. The remainder were treated with adjunctive
radiosurgery and steroid inhibitors. One patient was treated with adrenalectomy.
In addition, of the 264 patients with non-functional tumors, 14 (5.3%) have had
recurrent, growing tumor on subsequent surveillance imaging. These patients were
treated with a second debulking transsphenoidal resection, followed by radiosurgery.
Complications:
Complications are listed in Table 5. No carotid injuries occurred. There was one
spontaneous subarachnoid hemorrhage from peri-operative rupture of a basilar artery
aneurysm.
Table 5 Complications
Discussion:
A number of lessons can be derived from this 10-year experience. First, the endoscopic
approach has been confirmed to be both a safe and effective means of removing tumors
and other pathologies in this region. The concerns about the increased risk of a
paramedian approach have been eliminated, as no injury to critical structures were
encountered as a result of this approach. There were no carotid injuries, and the small
number of patients in whom visual worsening occurred likely experienced this as a result
of interruption in blood supply to the chiasm from tumor removal, not from any risk of
the use of the endoscope in the approach. The complications encountered with this
revised endonasal endoscopic technique are not in excess of those generally quoted for
standard transsphenoidal surgery. (2,7) No return to surgery for repair of CSF leak
occurred.
The efficacy of the approach has also been confirmed in this series. The recurrence rate
is compatible with those reported for standard sublabial resection of such tumors. The
recurrence rate for secretory tumors remains undesirably high. This appears to be due to
local invasion of the dura and cavernous sinuses, rendering complete removal of such
tumors impossible without unacceptable neurologic deficit. For the foreseeable future,
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adjunctive therapy with antagonist medications and /or radiotherapy will be the norm
for such lesions.
Conclusion:
The goal of this report is to describe the technique and results for surgery of the sellar
region using an endonasal endoscopic approach. This 10-year experience demonstrates
efficacy and safety which is comparable to the standard sublabial approach. Given the
readily observed improvement in patient comfort for this minimally invasive technique
over that experienced by patients undergoing the sublabial approach, the endoscopic
approach and resection of sellar lesions may become the procedure of choice for such
lesions.
REFERENCES
1. Cappabianca P, Cavallo LM, de Divitis E: endoscopic endonasal transsphenoidal
surgery. Neurosurgery, 2004 Oct;55(4):933-40; discussion 940-1.
2. Ciric I, Ragin A, Baumgartner C, et al: Complications of transsphenoidal surgery:
Results of a national survey, review of the literature, and personal experience.
Neurosurgery 40:225-237, 1997.
3. Coldwell WT, Weiss, MH: Transnasal transsphenoidal approach, in Apuzzo MLJ (ed):
Surgery of the Third Ventricle. Baltimore: Williams and Wilkins, 1998, pp 553-574.
4. Cushing H: The Weir Mitchell lecture. Surgical experiences with pituitary disorders. Jama
63:1515-1525, 1914.
5. Hardy J: Transsphenoidal microsurgery of the normal and pathological pituitary. Clin
Neurosurg 16:185-217, 1969.
6. Jho HD, Alfieri A: Endoscopic endonasal pituitary surgery: Evolution of surgical
technique and equipment in 150 operations. Minim Invas Neurosurg 44:1-12, 2001.
7. Laws ER, Kurn EB: Complications of transsphenoidal surgery, in Tindall GT, Collins WF
(eds): Clinical Management of Pituitary Disorders. New York: Raven Press, 1979, pp 435445.
8. Semple PL, Laws ER, Jr.: Complications in a contemporary series of patients who
underwent transsphenoidal surgery for Cushings disease. J Neurosurg 91:175-195,
1999.
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Introduction
Pituitary tumors represent the third most common primary brain neoplasm and
constitute 10 15% of intracranial tumors in most surgical series, afflict both sexes
equally and most commonly present in the 3rd 6th decade of life. Radiological reports
indicate that with the more widespread use of MRI, 10 -15% of MRI brain scan
demonstrates some abnormality of the pituitary gland. Necropsy series show an incidence
of 20-25% of pituitary lesions, suggesting that many of these lesions are asymptomatic
during life.
The first account of the surgical management of a pituitary tumour is accredited to Dr.F.T.
Paul. He was a British general surgeon, who in 1892, treated a 34yr old acromegalic female
patient. She presented with headaches, facial pain and visual loss. Following a consultation with
Sir Victor Horsely, Paul preformed a subtemporal decompression. He was unable to resect the
tumor but was able to reduce intracranial pressure, affording some symptomatic relief. The
patient died 3 months later and at time of necropsy, a tangerine sized pituitary tumor was found,
the size suggesting suprasellar extension. Horsely preformed the first resection of a pituitary
tumor via a transcranial approach in 1899.
Although pituitary lesions are the commonest pathology to be found in the sellar &
suprasellar space, other lesions that should be considered in the differential diagnosis
include meningiomas, cell rest lesions(Rathke cysts; Craniopharyngioma; Chrodoma),
vascular (aneurysms) lesions, Lymphoma, metastesis, glial tumors, germ cell tumors
(Germinomas; Teratomas), dermoid & epidermoids, granulomatous inflammatory
(Sarcoid; Lymphhocytic hypophysitis) and infectious conditions (tuberculosis; abscess,
neurocysticercocis).
Pathology:
Pituitary tumors can be classified in various ways. These may be on 1) anatomical basis
by size {micro-adenomas (<10 mm) or macro-adenomas ( 10 mm)} or radiologically
or on 2) histological basis with immunohistological characterization of the lesions or on
3) functional basis with endocrine active (functioning) or endocrine silent (nonfunctioning) lesions.
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Stage II
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is a neurosurgical emergency.
Pre-op work-up:
All patients need to be fully worked-up pre-operatively. This is especially relevant in
pituitary lesions where the secondary effect of the endocrinopathy may influence the
outcome. All patients need a full pituitary endrocine profile and relevant blood testing
done as per the concurrent co-morbidities. Referral to an endocrinologist may be
needed. Imaging study of choice is a MRI brain scan pre and post contrast. Tumors are
usually iso to hypo intense on T1 weighted sequences and enhance with contrast
administration. On T2 weighted sequences, the lesions appear hyper-intense. This will
allow careful evaluation of the anatomic structures with particular assessment of the visual
apparatus, vascular structures and the pituitary gland. A CT brain scan, although less
accurate than a MRI, may be of benefit to assess bone invasion, sphenoid air sinus
anatomy and identification of calcification. A plain skull X-ray may show an enlarged
eroded sella. An anaesthetic consult is indicated as co-morbidities and secondary effects
of the tumor may complicate and impact the anaesthetic process.
Surgery:
Although the preferred access to pituitary tumors is the transsphenoidal route, 1-4%
of pituitary tumors still require a craniotomy for optimal management.. With the
tumor mostly midline, the transshenoidal route would still be the approach of choice
regardless of the size and extent of suprasellare extention. . This affords excellent
opportunity for gross total removal of the tumour. Intra-operative Valsalva manoever (up
to 35 mm Hg) may assist in helping deliver the supra-sellar tumor bulk.
Some surgeons have also utilized a pre-operatively placed lumbar catheter to further
increase the subarachnoid pressure with injections of saline. Once the arachnoid has been
breached the latter two techniques are not helpful. Tumor is then removed using a variety
of angled currettes and suction. Even large tumors with a postero-superior extension can
be delivered this way especially if the tumor is soft. With larger more fibrous lesions full
delivery of the supra-sellar component may be more difficult. Any CSF leak is repaired.
This is done with the help of a fascia lata graft followed by a fat plug. A vascularized nasoseptal flap has also proven to be very effective in sealing large CSF leak. This flap is kept
in place post- operatively with a foley cather inflated to 10 cc for 2 3 days.
Unfortunately there are lesions that do not conform to in-line supra-sellar extention.
These lesions should be considered for an alternative surgical approach. These include
transcranial approaches and combination transcranial transsphenoidal approaches.
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Suprasellar region
3)
4)
5)
6)
7)
Lateral extention into the cavernous sinus is a problem that is encountered with
both secretory and non-secretory lesions. The necessity to gain complete tumor
clearance will dictate the aggressiveness of the approach. The indication for this
may be either decompression of a neuropathy or potential cure for an
endocrinopathy. Further lateral expansion into the middle cranial fossa mandates
a transcranial route.
Inaccessible Suprasellar Extension
Extension onto the Planum Sphenoidale and encasement of optic nerves /
apparatus and arteries as well extension lateral to the carotid arteries is a
common indication for transcranial surgery.
Fibrous Pituitary Adenoma with Large Suprasellar Extension
Tumors may be unpredicatably very fibrous and resist excision via the
transsphenoidal route. The ability to predict this on imaging studies is very
limited. Some 5 7.5% of pituitary tumors are found to be fibrous in nature
(Snow, 1986, p01511). This complicates endonasal resection of the lesions as
these lesions do not collapse during valsalva and surgical removal. An expanded
transsphenoidal approach may be indicated. Imaging signal on T1 & T2
weighted MRI scanning may provide a suggestion that a lesion is more likely to
be fibrous in nature.
Active Sinus Infection
This is only of relevance if the surgery is acute and the associated sinus infection
is severe.
Co-existence of Pituitary Adenoma and Adjacent Aneurysm
This unusual presentation will dictate the use of a transcranial approach. The
relevance of this is for Anterior communicating artery aneurysms that would be
treated surgically.
Ectatic Intrasellar Kissing Carotid Arteries
Rarely seen but more commonly so in acromegaly.
Surgery for these lesions are challenging and need careful consideration and planning.
Mortality rates for large pituitary lesions with suprasellar extension was initially reported8
as 35% prior to the microsurgical era. The morbidity and mortality of the surgical
management of these lesions have decreased over the last couple of decades. Large
lesions tend to adhere to adjacent neural structures in addition to infiltration and
invasion of the cavernous sinus and surrounding structures.
In selected cases a staged surgical resection of the tumor can be planned, the initial
procedure relieving the acute compressive symptoms. The goal of surgical management
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is the safe decompression of neural tissue at risk with the aim of complete tumor
excision.
Adjuvant Therapy:
Other forms of treatment may be considered in this setting. Pharmocologic therapeutic
options include the use of Bromocriptine or Dostinex,, dopamine agonist agents. These
tumors respond to Bromocriptine with reduction in prolactin production, reduced
metabolic activity of the tumor and shrinkage of the lesion. Medical therapy is the
initial treatment of choice in prolactinomas regardless of their size. The reduction in size
may be early and dramatic. The indications for surgery in patients with giant
prolactinoams include intra-tumoral hemorrhag with rapid visual loss or patients who
have deterioration of their vision despite being on dopamine agonist9.
The same would hold true for radiotherapy. Stereotactic radiosurgery may be of benefit
as an adjuvant therapy post surgery but as a primary treatment modality of large
pituitary lesions is usually not indicated. The close proximity of the optic apparatus and
the pituitary gland also limits the dose that could be used. The option to use radiotherapy
as a follow-up treatment for residual tumor is an option.
REFERENCES
1) BERND W. SCHEITHAUER et al; Pathology of invasive pituitary tumors with special
reference to functional classification; J Neurosurg 65:733-744, 1986
2) Pamela U. Freda, Kalmon D. Post;DIFFERENTIAL DIAGNOSIS OF SELLAR MASSES,
Endocrinology and Metabolism Clinics - Volume 28, Issue 1 (March 1999)
3) Amir R. Dehdashti, Ahmed Ganna, Ian Witterick, Fred Gentili, EXPANDED
ENDOSCOPIC ENDONASAL APPROACH FOR ANTERIOR CRANIAL BASE AND
SUPRASELLAR LESIONS: INDICATIONS AND LIMITATIONS; Neurosurgery
64:677689, 2009
4) Benjamin C.P. Lee, Michael DF. Deck, Sellar and Juxtasellar Lesion Detection with MR;
Radiology 1985; 157:143-147
5) Yona Greenman, Shlomo Melmed, DIAGNOSIS AND MANAGEMENT OF
NONFUNCTIONING PITUITARY TUMORS, Annu. Rev. Med. 1996. 47:95106
6) L Symon, J Jakubowski, Transcranial management of pituitary tumours with suprasellar
extension,J. Neurol. Neurosurg. Psychiatry 1979;42;123-133
7) A. Samy Youssef, Siviero Agazzi, Harry R. van Loveren, TRANSCRANIAL SURGERY
FOR PITUITARY ADENOMAS, Neurosurgery 57[ONS Suppl 1]:ONS-168ONS-175,
2005
8) Jefferson,G, Extrasellarextensionsofpituitaryadenomas.President's address. Proceedings
of the Royal Society of Medicine 33:433-458, 1940
9) RAJ K. SHRIVASTAVA, MARC S. ARGINTEANU, WESLEY A. KING, KALMON D.
POST, Giant prolactinomas: clinical management and long-term follow up, J Neurosurg
97:299306, 2002
10) King WA; Rodts GE; Becker DP; Mc Bride DQ; Microsurgical management of Giant
Pituitary Tumors, Skull Base Surgery 6(1):17-26, 1996
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Pituitary adenomas are benign tumors composed of anterior pituitary cells. They
display an array of hormonal and proliferative activity. Their hormonal activity is
usually reflective of their cytodifferentiation, which can mimic some of the known cell
types of the anterior pituitary. Pituitary adenomas identified in patients with no evidence
of hormonal hypersecretion are referred to as clinically nonfunctioning adenomas
(NFAs), and they account for approximately 30 to 40% of all pituitary tumors.
Advances in radioimmunoassay, immunocytochemistry and molecular biology
techniques have enabled to determine that most clinically nonfunctioning adenomas,
formerly identified as chromophobic, are in fact producers of gonadotropins or some of
their subunits.
Glycoprotein hormones, including the luteinizing hormone (LH), folliculo-stimulating
hormone (FSH) and thyroid-stimulating hormone (TSH), are heterodimers consisting
of a common alpha subunit and a beta subunit which is unique for each hormone
and which determines its biologic specificity. These tumors can produce intact LH or FSH
or monomers of the alpha- or beta-subunits, which can be detected in vivo or in vitro
depending on available techniques. Differences in the frequency of detection of
gonadotropin subunits may be due to variations in the sensitivity and specificity of such
techniques. Most of these tumors are macroadenomas, which are sometimes highly
invasive. Since, production of gonadotropins does not generally confer a characteristic
clinical phenotype, signs and symptoms are reflective of the tumor mass effect. They may
cause visual disturbances resulting from optic nerve compression or other neurological
signs and symptoms, or deficiency of other anterior pituitary hormones (either partial
or complete hypopituitarism). Consequently, these adenomas are often not recognized
until they become large enough to cause neurological symptoms.
All pituitary adenomas, including nonfunctioning and gonadotroph adenomas, are of
monoclonal origin. They arise from the somatic mutation of a single stem cell, which then
proliferates; however, the mutation causing the transformation remains unknown (1), (2).
Genetic mutations that might be directly or indirectly related to pituitary adenoma
development, including genes expressing proto-oncogenes such as c-myc, c-fos and cmyb, have been investigated (3), (4). C-myc proto-oncogene is over expressed in a subgroup
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of pituitary tumors. C-fos overexpression is less common, and c-myb does not appear to
have a role in the pathogenesis of pituitary tumors. Point mutations of ras oncogen and
of p53 do not appear to play a major role (5), (6), since they were only found in some isolated
tumors.
Should nonfunctioning adenomas (NFAs) be classified only by using conventional
microscopy techniques with hematoxylin and eosin staining, most of them would
correspond to the so-called chromophobic adenomas.
Approximately 25% of pituitary tumors are not associated with hormonal
hypersecretion which can be detected peripherally, and they are referred to as clinically
nonfunctioning or silent adenomas. Within this group, gonadotropinomas are the
most common, and are considered to be silent due to the frequent absence of signs and
symptoms of hypergonadotropism or of increased serum gonadotropin levels.
Gonadotropinomas are basically classified by immunocytochemistry rather than by
clinical features (7). They typically show immunoreactivity for the alpha subunit as well as
for FSH- and LH-beta subunits, or both.
Many NFAs are classified as null cell adenomas (i.e. non-detectable by
immunostaining for any hormone). However, we now know that these adenomas are
capable of secreting hormone alpha and/or beta-subunits in in- vitro cell culture
conditions (8). Molecular biology studies have confirmed the presence of genes expressing
glycoproteins. These data would prove that null cell adenomas are in fact silent
gonadotropinomas with very low expression of immunoreactivity. These tumors show
a very diffuse histological architecture, but if thoroughly analyzed, typical characteristics
of silent gonadotropinomas will be found. In addition, high affinity antibodies should be
used in order to avoid false negatives when performing immunostaining.
These adenomas have been shown to express the gonadotroph-associated transcription
factor SF-1, which, as mentioned above, would suggest the gonadotrophic cell activity of
the adenoma (9). In addition, electron microscopy reveals characteristic ultrastructure
features similar to those of gonadotropinomas. There is strong evidence that most
null cell adenomas have hormonal secretory capacity, with most of them being
defined as silent gonadotropinomas. This has led to a change in the clinical definition of
these NFAs.
On the other hand, other types of tumors forming a subgroup referred to as
plurihormonal tumors, as defined by Kovacs et al, have been identified (10). These
adenomas are characterized by the fact that they simultaneously immunostain for
several hormones, most frequently growth hormone (GH), prolactin (PRL) and alphasubunit. These tumors have obviously no clinical expression of hormonal
hyperfunctioning. The etiopathogenesis of this subgroup is not well-established,
suggesting that multihormonal expression may be due to transcriptional causes, receptor
mutations, or other causes (7,11,12,13). These tumors include silent GH (14), silent PRL (15), silent
TSH (16), and silent adreno-corticotrophic hormone (ACTH) adenomas (17), which may
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Suprasellar region
immunostain for other proopiomelanocortin (POMC) derivatives. Patients with silent
ACTH adenomas may present with hyperprolactinemia, with no evidence of pituitary
stalk section or disconnection. In sum, nonfunctioning pituitary adenomas include
various types of increasingly better classified tumors, among which gonadotropinomas
are the most frequently found, with clinically silent gonadotropinomas being the most
prevalent.
CLINICAL PRESENTATION
The presence of a pituitary adenoma with no clinical symptoms of acromegaly,
Cushings disease, or hyperprolactinemia is suggestive of a potential nonfunctioning
pituitary adenoma, which could correspond to a gonadotropinoma.
As mentioned above, gonadotroph adenomas rarely result in clinically recognizable
hormonal hypersecretion, and are therefore also referred to as clinically nonfunctioning
adenomas. However, in 1989, Haseltine et.al., (18) reported on cases of macroorchidism in
male patients with gonadotroph adenomas with FSH hypersecretion, highlighting that
these adenomas may also have clinical manifestations.
The most common manifestations of tumor mass effect include headaches, visual field
impairment and some degree of pituitary insufficiency. Cranial nerve abnormalities,
syndromes related to invasion of cavernous sinuses and pituitary apoplexy are less
common.
In a series of 26 patients with NFAs, Arafah et. Al., (19) described the different clinical
manifestations at diagnosis, with 42% of patients presenting with serious visual
impairment; 23% with persistent headaches; 23% with decreased libido or impotence,
and 12% with lassitude and fatigue.
In another series of patients, Harris et. al., (20) showed that 73% of cases had some degree
of visual field impairment. In fact, most studies on this subject, though showing
different percentages, prove that at diagnosis visual impairments are caused by chiasmal
compression resulting from the large size of the tumor. As a result, most patients also have
hypopituitarism. In some series, such as Arafahs review (19), hypogonadism was found in
96% of these patients, secondary hypothyroidism in 81%, and adrenal insufficiency in
61%.
Some of these patients present with a certain degree of hyperprolactinemia resulting
from the compression of the pituitary stalk or hypothalamic structures, leading to a
disconnection and thus increased pituitary PRL secretion, rarely exceeding 100 ng/ml.
This often makes the diagnosis of tumor etiology difficult, leading to suspicion of a
prolactinoma, more even so when PRL levels are close to or above 100 ng/ml. Occurrence
of diabetes insipidus is uncommon in spite of the large size and invasiveness these
adenomas may show. If diabetes insipidus does occur, it might suggest a different
etiology from that of a pituitary tumor, which should be considered in the differential
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diagnosis.
The clinical presentation of these adenomas can be schematized by dividing it into
three basic aspects: (21)
1. Ophthalmological and/or neurological manifestations
2. Imaging findings
3. Expression of hormonal abnormalities
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causing diplopia and/or palpebral ptosis, among others.
In large macroadenomas, atypical expansions to the cerebral hemispheres and/or
ventricles may also be found. In some cases, their growth may involve the brainstem.
Extension to the sphenoid sinus may also be seen, with bone structure loss in the sellar
region, sometimes causing spontaneous rhinorrhea, which is an indication of the
sphenoid and sellar floor loss.
As a result of such tumor invasion, one of the most common symptoms and chief
complaints in over 90% of cases are headaches which often radiate to the whole calvaria,
with sometimes very insidious features and a poor response to commonly prescribed
pain-killing drugs.
These large tumors are very rarely associated with diabetes insipidus in spite of the
pituitary stalk compression and the large invasion of the hypothalamic region, with
preservation of the paraventricular and supraoptic nuclei. When this occurs, it may be
due to a non-adenomatous tumor.
Thus, such highly invasive NFAs or gonadotropinomas have a poor prognosis
regarding postsurgical complications and the potential persistence of non-resectable
tissue, which in turn lead to recurrence or regrowth, unfortunately putting the patients
life at a serious risk.
Due to their aggressiveness, attempts have been made to identify these highly invasive
tumors with some better defined type of tumor, but up to date it has been difficult to
distinguish them from other NFAs because of the absence of a specific marker. On the
other hand, and because of the lesion severity, they do not fall into the definition of
pituitary adenocarcinomas.
2- Imaging Findings
The finding of a tumor area in the sellar region gives rise to two possibilities that should
be considered at the time of diagnosis.
The first is an incidental finding in the absence of specific symptoms of a pituitary
disorder when magnetic resonance imaging (MRI) or computerized tomography (CT)
scans are performed for another lesion or other purposes. This incidentally discovered
mass is defined as an incidentaloma. This finding is usually typical of a grade I or II
adenoma which has yet no clinical manifestation associated with pituitary dysfunction
and which due to its frequency is more commonly associated with a NFA in the early
stages. Tumors of invasive size are less common, although cases have been described
within this group.
Up to date, the best imaging modality is brain MRI, with slices focused on the
hypothalamic-pituitary region, particularly with a paramagnetic contrast agent. It must
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2a
2b
Fig. 2 Invasive Adenoma Grade IV
Another possibility is to perform a CT scan with iodinated contrast, but it affords less
definition and has virtually fallen into disuse for the diagnosis of pituitary adenomas.
However, once diagnosis has been made through MRI, in certain special situations
CT scans provide surgically useful information since they allow better definition of
bone structures.
MR angiography is another diagnostic modality that may be required. It is useful for
the differential diagnosis with vascular processes such as aneurysms of the sellar region,
which may mimic adenomas.
Arteriography might also be required if there is strong suspicion of an aneurysm or
other vascular abnormality.
Finally, and almost as a historical review, we will refer to the radiography of the
sellar region. At one time, it may have been the only modality to provide information that
would suggest the presence of a pituitary adenoma. Nowadays, it has been displaced by
MRI; however, in the presence of morphological changes or deformity of the sellaturcica, it may lead to the detection of a potential space-occupying process in a simple,
rapid and low-cost way, although it does not provide more accurate information (Fig. 3).
In sum, according to different statistical data, most of the NFAs found show sellar and
suprasellar expansion in 50 to 70% of cases; the remaining tumors extend into the
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Suprasellar region
3- Hormonal abnormalities
The clinical expression of hormonal abnormalities in NFAs can be schematized by
dividing it into two aspects:
a) Symptoms of pituitary insufficiency
b) Symptoms of hormonal hypersecretion
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DIAGNOSIS
Initially, diagnosis will consist in the assessment of three basic aspects:
1. Pituitary function
2. Tumor mass
3. Visual field
MANAGEMENT
Since gonadotroph adenomas are usually not detected until they become large
enough to cause significant visual impairment, treatment should be aimed at reducing
the size of the adenoma and restoring vision as soon as possible. So far, transsphenoidal
surgery is the only approach meeting this criterion.
Gonadotroph adenomas are usually sensitive to radiation therapy; therefore,
postoperative radiation therapy may be attempted in order to avoid recurrence, if a
surgically inaccessible tumor remnant persists.
Several pharmacological therapies have been attempted, but none of them has shown
marked tumor reduction.
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SURGERY
Transsphenoidal surgery is usually the procedure of choice for pituitary adenomas. It
is preferred to transcranial surgery as initial treatment because adenomas are infradural
and there is less risk of morbidity and mortality or side effects.
Another intervention now in use is endoscopic surgery. The transcranial route may be
reserved for use in a later stage, when neurological symptoms persist due to partial
resection of the adenoma with the transsphenoidal approach.
SURGICAL APPROACHES
TRANSSEPTAL-TRANSSPHENOIDAL APPROACH
In 1910, Oskar Hirsch, an otorrhinolaryngologist from Austria, described the
endonasal transeptal-transsphenoidal approach.(1) Also in 1910, Albert Halstead, in
Chicago, described the sublabial-gingival approach.(2) Harvey Cushing initially used
the transcranial approach (8 subtemporal and 5 subfrontal approaches); however, since
he achieved poor results, he adopted the transsphenoidal route,(3) thereby becoming the
first surgeon to perform a sublabial-gingival transsphenoidal approach to the pituitary
gland. He used the transsphenoidal approach between 1910 and 1925, operating on 231
patients with pituitary tumors, with a mortality rate of 5.6% (Figure 4 a and b) From 1929
onwards, however, Cushing abandoned the transsphenoidal route and came to favor the
transcranial route.(4) Norman Dott, a disciple of Cushing's, continued to perform the
transsphenoidal approach in Scotland and eventually introduced a speculum with a builtin light. Gerard Guiot, from France, visited Dott in 1956 and learned the transsphenoidal
technique from him.(5) That year, Dott performed 80 consecutive operations with the
transsphenoidal approach, with no deaths. In subsequent years, Guiot started to refine
the transsphenoidal approach by introducing intraoperative radiofluoroscopy.(5) Driven
by his pioneering spirit, Guiot applied the transsphenoidal approach to the treatment of
craniopharyngiomas, clivus chordomas and parasellar lesions. Jules Hardy, from Canada,
learned this procedure from Guiot. In 1967, Hardy adopted the surgical microscope for
4a
Fig. 4 Cushing Approach
4b
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415
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Suprasellar region
the floor. Importantly, the head should be well fixed to the head-holder with adhesive tape
in order to prevent any intraoperative movements. One major advantage of the halfseated position is that it frees the surgical field from blood, since any kind of potential
bleeding falls on account of gravity and does not interfere with the surgeon's view.
The patient is given general anesthesia with endotracheal intubation and to prevent blood
ingestion a pharyngeal packing is used.
Preparation
After occluding the eyes with adhesive tape, the nose, the nasal area and the gingival
mucosa are prepped with antiseptic solution (Pervinox solution). When the tumor
has a suprasellar extension, the lower right quadrant of the abdomen is also prepped to
harvest a fat graft to pack the sella turcica after tumor excision in order to prevent the
potential development of a cerebrospinal fluid (CSF) fistula. Surgical drapes are then
placed and the surgical microscope is positioned.
Surgical Technique
As the surgical assistant (standing to the left of the surgeon) separates the lateral border
of the right naris, the surgeon infiltrates the septal mucosa with 1% xylocain containing
epinephrine and then performs a 1.5-cm-long vertical incision through the septal
mucosa. The septal mucosa is then separated from the nasal septum with the help of a
dissector. This is an easily performed maneuver since the mucosa has been partially
detached from the nasal septum with the aid of a previous xylocain infiltration. The
dissection is continued deeply until reaching the proximity of the attachment of the
perpendicular plate of the ethmoid bone and the vomer with the sphenoid body; at that
point, the bone septum is broken and moved from the midline (this maneuver is
performed by opening and rotating the manual speculum to the right). Once reaching
the midline, an autostatic speculum is placed and fully opened to maintain retraction of
the nasal mucosa outside the field of view. The following step involves identifying both
sphenoidal sinus foramina and removing symmetrically the anterior wall of the sphenoid
bone. This leads us inside the sphenoidal sinus; the thin sinus mucosa is wholly removed
when there is evidence of inflammatory or infectious changes. Otherwise, removal is only
partial.
When one or more bone septa hinder the exposure of the sellar floor, removal of these
septa is required to fully expose the posterior aspect of the sinus and the floor of the sella
turcica. Wherever possible it is advisable to obtain a small piece of bone (from the
vomer or bone septum), measuring approximately 1 cm 1 cm, to repair the floor of the
sella turcica. With the microscope pointing directly to the anterior lower surface of the
sella turcica, and with the help of a small chisel, the sellar floor is opened from midline
to lateral, creating a 1.5-cm wide 1-cm long window. When the lesion is a
macroadenoma with sella turcica enlargement, the sellar floor will be extremely thinned
or partially absent. Sellar dura mater may also be thinned owing to tumor growth.
The next step involves a cruciate incision of the sellar dura up to the margins of the bone
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opening; this is done with a bayonet-shaped knife holder. In most cases, after opening the
dura and as a consequence of intrasellar pressure, grayish tumor tissue is expressed and
should be removed with punch forceps for pathology examination. The remaining
adenoma is dissected with differently angled curettes, directed in all orientations, plus a
surgical aspirator. As soon as the sellar cavity has been emptied, the suprasellar extension
of the tumor will move downward spontaneously towards the sella turcica and as a result
of normal intracranial pressure. If this does not happen, intracranial pressure may be
increased by applying compression to both internal jugular veins. At the end of the tumor
excision procedure, the surgeon should perform a thorough exploration of the whole
cavity to check for complete removal of the lesion and preservation of the normal
gland. It is at this point that endoscopic assistance becomes highly useful, using a 30- or
60-angulated view endoscope.
After correct hemostasis is achieved, the piece of bone previously taken from the vomer
is used to cover the sellar bone defect and fixed with methylmethacrylate. Finally, the nasal
septum is moved back to its normal position and both nares are packed.
6b
6a
Fig. 6 Transphenoidal with Endoscopic Assistance
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Suprasellar region
In these cases, the microsurgical approach can be directly transnasal, i.e. righthanded surgeons access the mucosa directly through the right naris to perform an
incision anteriorly to and along the sphenoid ostium, at the level of the middle nasal
turbinate. After locating the anterior aspect of the sphenoid bone body, the vomer
attachment is broken and the septum displaced towards the contralateral side, in order
to get a better view of the area with a surgical microscope. At that point, the endoscope
is angled at 30 or 60 into the cavity for inspection of the sphenoidal sinus and
recognition of bone indentations corresponding to the carotid arteries or optical nerves.
When this mixed approach is applied, at this point it is advisable to switch to the
ordinary microsurgical technique and subsequently open the sellar floor and the dura,
and, then, excise the tumor. When adenomas are large in size it is important that the
endoscope be relocated at the end of the procedure in order to observe the residual cavity
for any tumor remnant, which should be completely excised, or openings that might lead
to the development of a CSF fistula. Finally, closure should be performed with an
appropriate technique, in order to prevent complications, especially CSF fistula.
Radiation Therapy
Radiation therapy may be beneficial in patients for whom surgery is contraindicated
or whose tumors are surgically inaccessible, as well as in those with significant tumor
remnants after surgery.
The most commonly used radiation therapy is the standard approach with a linear
accelerator in a total dose of 45-50 Gy delivered during several weeks with a supervoltage
source. Other techniques which employ various radiation sources delivered
stereoctactically to attempt to minimize the amount of radiation to which the brain is
exposed have been used. Stereotactic radiation surgery involves stereotactic delivery of
a single, high dose of radiation from one of several possible sources, including protons
from a cyclotron or from a linear accelerator.
No controlled studies have been performed investigating tumor recurrence rates in
patients treated with postoperative radiation therapy, as compared to patients treated only
with surgery. Decision to administer radiation therapy depends on the tumor size, its
closeness to the optic chiasm (radiosensitive tumors located very closely to the chiasm
may result in neuritis or radiation necrosis) and the need to preserve pituitary function.
After radiation therapy, there is a significant incidence of pituitary dysfunction. Infertility
is a potential complication, although fertility may be recovered by means of gonadotropin
therapy. Young patients who wish to have children often decide not to undergo radiation
therapy.
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Pharmacological Management
Dopamine Agonists
Several studies have shown the presence of dopamine receptors in NFAs. D2 receptors
are the most commonly expressed. Cabergoline administration in vitro inhibited alpha
subunit levels in 56% of cases, and these results have been associated with D2 expression
(Pivonello et al 2004). However, in spite of dopamine receptor expression in these
tumors, tumor size reduction or visual field improvement are uncommon in NFAs
treated with dopamine agonists.
Somatostatin Analogues
It has been shown that somatostatin receptors are overexpressed in all pituitary
adenomas, with a predominance of sst2 and sst5 and infrequent expression of sst4. In
NFAs, the most commonly expressed receptor subtype is sst3, followed by sst2. A few
clinical trials have been performed to assess the potential effect of octreotide in patients
with NFAs.
In Colaos recent review (2008) of 11 published series, only 5 out of 100 patients (5%)
achieved tumor reduction.
Therefore, although the presence of somatostatin receptors in NFAs has been
demonstrated, treatment with somatostatin analogues was not found to be effective in
tumor reduction.
Surgery-related complications
Complications occur in <1% of the cases and are associated with anatomical
manipulation during surgery (24 and 25). They can be immediate or mediate complications:
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Suprasellar region
Immediate Complications
a) Worsening of visual symptoms: Secondary to compression of the optical nerves
during surgery or owing to the postoperative development of hematoma.
b) Injury of the intracavernous carotid artery.
c) Intracranial hematoma: Subdural, extradural or intraparenchymal.
d) Brain ischemia: Secondary to vascular injury.
e) CSF fistula
Mediate Complications
a) CSF fistula
b) Postoperative meningitis
We will focus exclusively on the diagnosis and management of CSF fistula because we
have practically never encountered the above mentioned complications throughout
our experience.
In patients who were treated with a transsphenoidal approach, CSF fistula diagnosis
is established mainly when tamponades are removed. It is commonly confirmed by
evaluating nasal secretion with blood glucose-measuring test strips. Once a fistula has
been clinically diagnosed, prophylactic antibiotics should be avoided to prevent
meningitis: this generates a selection of nosocomial bacteria which require broaderspectrum and longer-lasting therapies with antibiotics. These fistulae tend to close
spontaneously in the course of 48-72 hours. If closure does not occur, however, a
continuous lumbar drainage for 48-72 hours can be attempted. Radioisotope
cisternography, metrizamide-enhanced CT scanning, intravenous gadolinium-enhanced
MRI or even intrathecal gadolinium-enhanced MRI can be performed to confirm
fistula closure. Surgical repair will be considered on the basis of the results obtained with
these imaging methods.
Neuroendocrine References
1. Herman V Fagin J, Gonsky R, Kovacs K and Melmed S. Clonal origin of pituitary
adenomas. J. Clin. Endocrinol. Metab, 1990, 71:1427-1433.
2. AlexanderJ. M., Biller B.M.K., Bikkal H. etal. Clinically nonfunctioning pituitary tumors
are monoclonal in origin. J. Clin. Invest, 1990,86: 336-340.
3. Woloschak M, Roberts J. L. and Post K. Crnyc, C-fos and cmyb gene expression in
human pituitary adenomas. J. Clin. Endocrinol. Metab, 1994,79:253-257.
4. Chernavsky A.C., Chervin A.B., Vitale M., Basso A. and Burdman J. A. Human pituitary
tumours: studies on genes expression. Neurol. Res, 1993,15:2-6.
5. Cai W. Y, Alexander J. M., Hedley Whyte E. T. et al. Ras mutations in human
prolactmomas and pituitary carcinomas. J. Clin. Endocrinol. Metab,1994, 78: 89-93.
6. Pei L., Melmed S., Scheithauer B., Kovacs K. and Frager D. H-ras mutations in l1M,man
pituitary carcinoma metastases. J. Clin. Endocrinol. Metab, 1994,78: 842-846.
7. Yoshimoto K., Iwahana H., Fukuda A. et al. Rare mutations of the Gs alpha subunit gene
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
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Surgical References
1. Hirsch O: Endonasal method of removal of hypophyseal tumors. With a report of two
262 Neuro-oncology
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successful cases. JAMA 55:772-774, 1910.
2. Halstead AE: Remarks on the operative treatment of tumors of the hypophysis. With the
report of two cases operated on by an oro-nasal method. Surg Gynecol Obstet 10:494502, 1910.
3. Welbourn RB: The evolution of transsphenoidal pituitary microsurgery. Surgery
100:1185-1190, 1986.
4. Liu JK, Das K, Weiss MH, Laws ER Jr, Couldwell WT: The history and evolution of
transsphenoidal surgery. J Neurosurg 95:1083-1096, 2001.
5. Guiot G: Transsphenoidal approach in surgical treatment of pituitary adenomas:
General principles and indications in nonfunctioning adenomas. En Kohler PO, Ross GT,
editores: Diagnosis and treatment of pituitary tumors. New York, 1973, American
Elsevier, pp 159-178.
6. Hardy J: Surgery of the pituitary gland, using the trans-sphenoidal approach.
Comparative study of 2 technical methods. Union Med Canada 96:702-712, 1967.
7. Hardy J: Transsphenoidal microsurgery of the normal and pathological pituitary. Clin
Neurosurg 16:185-217, 1969.
8. Basso, A. - Ameza, L. - Guitelman, A. - Ghersi, J. et Molocznic, I. Sndrome
Acromegalique- Choix de la technique chirurgicale Neurochirurgie, Pars, 19 (6) 537/544. 1973
9. de Divitiis E, Cappabianca P, Cavallo LM: Endoscopic transsphenoidal approach:
Adaptability of the procedure to different sellar lesions. Neurosurgery 51:699707,
2002.
10. de Divitiis E, Cappabianca P, Cavallo LM: Endoscopic endonasal transsphenoidal
approach to the sellar region. In: de Divitiis E, Cappabianca P (eds): Endoscopic
Endonasal Transsphenoidal Surgery. Wien, Springer Verlag, 2003, pp 91130.
11. de Divitiis E, Cappabianca P: Endoscopic endonasal transsphenoidal surgery, in Pickard
JD (ed): Advances and Technical Standards in Neurosurgery. Wien, Springer-Verlag,
2002, vol 27, pp 137177.
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Introduction
Acromegaly in the adult or gigantism in the young is mostly caused by a pituitary
adenoma secreting Growth Hormone (GH), which leads to a wide range of
cardiovascular, respiratory, endocrine, and metabolic morbidities with an increased risk
for all-cause mortality and decreased life expectancy (6). The estimated prevalence of the
disease is 40 cases/1000000 population with 3 4 new cases/1000000 population per year
(8). Normalization of GH and IGF-1 hormonal excess leads to a normalization of life
expectancy (6). Thus diagnosis and treatment of this condition which frequently young
patients is therefore of paramount importance.
Despite a number of advances in the medical management and endocrine diagnosis
of pituitary disorders, surgery remains one of the most effective ways of dealing with GHsecreting pituitary adenomas (5).
Diagnosis
Clinical symptoms
Acromegaly is thus defined from the Greek words that describe one of the most
apparent features of the patients: the enlargement (megan: large) of the extremities
(acros). The typical acromegalic patient has obvious facial features, which comprise frontal
bossing, supraorbital bulging, prognatism, enlarged nose, lips and tongue; The patient
frequently reports having had to change his/her shoes and rings size due to the
enlargement of feet and hands respectively (Figure 1). These obvious features are
frequently accompanied by signs of systemic involvement, as the disease affects the
cardiovascular, respiratory, endocrine, and metabolic systems (Figure 1). Patients with
a long- standing history, harboring a macroadenoma, can also present with signs of mass
effect by the pituitary adenomas, thus complaining of visual deficits due to compression
of the chiasm and signs of hypo-pituitarism due to pituitary gland distortion.
Biochemical findings
Elevated GH and IGF-I levels are the biochemical markers of acromegaly. GH levels
can present extreme variations due to the pulsatile secretion of the hormone, but
264 Neuro-oncology
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Suprasellar region
Neuroradiology
Magnetic resonance imaging (MRI) is the ideal imaging modality for pituitary
adenomas: a dynamic MRI, in which the sella is scanned at various times subsequent to
contrast administration, might be necessary to detect small microadenomas; fast spin echo
T2-images are also useful in the evaluation of microadenomas smaller than 3 mm (1).
Contrast administration can also be useful in macroadenomas to evaluate the location
of the compressed pituitary gland (Figure 2).
Computed tomography can be useful especially if a detailed study of the bone is
needed, e.g. in case of a conchal sphenoid sinus or complex sphenoid septations (9).
265
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266 Neuro-oncology
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Suprasellar region
Pre-operative assessment
A thorough ophthalmological examination should always be included if the patient
complains of visual disturbances and/or the pituitary adenoma presents with suprasellar
extension.
Due to the hypertrophy of structures in the pharyngeal region acromegalic patients
often suffer from sleep apnea and have a higher incidence of difficult intubation (7): a
pre-operative anesthesiological evaluation is therefore indicated.
The pre-operative assessment should include also a thorough cardiological evaluation
to rule out hypertrophic cardiomyopathy or other related cardiac disturbances. Tests
should be done to rule out abnormalities of the glucose metabolism and for
hypercalcemia (to rule out hyperparathyroidism, which can be rarely associated as
part of the Multiple Endocrine Neoplasia type 1).
Surgical treatment
The primary approach for treating GH-secreting pituitary adenoma is transsphenoidal
surgical resection (Figure 4). Achieving disease remission with surgery is highly dependent
on the experience and ability of the surgeon, tumor size and location, and preoperative
GH concentrations. Long-term surgical remission occurs in approximately 50 to 70% of
patients overall: it is more likely to occur in patients with microadenomas (up to 91%)
than in those with macroadenomas (approximately 50%) (10). A pure endoscopic
endonasal technique is becoming the mainstay in transsphenoidal surgery (2) (Figure 3):
it is usually well tolerated and has the advantage of a wider and better illuminated
field of view provided by the endoscope. In acromegalic patients, though the nasal
cavities can be larger than usual, mucosal hypertrophy has to be anticipated and can be
dealt with topical application of vasoconstrictors.
The pituitary adenoma is typically whiteish and of soft consistency and easily suckable.
Careful exploration of the surgical cavity in search of remnants and portions of pseudocapsule is important to achieve complete surgical excision with hormonal remission.
Intraoperative guidance (CT or MRI based neuronavigation; if not available,
intraoperative fluoroscopy) can be helpful, especially in case of recurrent tumors, when
normal anatomy can be distorted; It is also very useful in cases of anatomical variants that
obscure the classic anatomical landmarks, e.g. in case of a conchal sphenoid sinus,
where sella, clivus, internal carotid artery and optic nerve protuberances are covered by
the non pneumatized bone of the sphenoid.
Occasionally, for invasive adenomas with large intracranial extensions a craniotomy
approach may be necessary.
Post-operatively careful assessment of fluid balance of the patient is important to rule
out diabetes insipidus, which, if it occurs, is frequently transient. If hypo-pituitarism was
evident prior to surgery corticosteroid coverage is mandatory. After endoscopic endonasal
transsphenoidal surgery, once a CSF leak has been ruled, the patient can be started on
nasal saline washes to minimize nasal crusting and facilitate the healing of the nasal
mucosa.
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268 Neuro-oncology
428
Suprasellar region
Fig. 4 Scheme of the therapy of acromegaly (modified from Melmed et al, 2009)(6)
Surgery remains the first line treatment for acromegaly.Medical therapy with somatostatin analougues
might be useful pre-operatively, when the general conditions contraindicate immediate surgical
intervention and no neurological symtoms are present. Adjuvant therapies are indicated in case of no
remission after surgery.
Legend: SRL: somatostatin receptor ligand; GHRA: GH receptor antagonist (Pegvisomant)
Adjuvant therapy
- Medical therapy
The main role of medical therapy is to achieve postsurgical long-term bio-chemical
control of the GH/ IGF-I axis, when surgery alone has not achieved remission(10).
Somatostatin analogs (i.e. octreotide, octreotide LAR, lanreatide) results in normalization
of IGF-I levels in approximately 50% of patients but may be associated with
gastrointestinal adverse effects, including the development of gallstones. Unfortunately,
some patients are suboptimally responsive to or become intolerant of these agents
(10). Recently a GH-receptor antagonist (pegvisomant) has been used in cases refractory
to somatostatin receptor ligands (SRL). This novel agent competitively binds to the GH
receptor, blocking IGF-I production effectively. Liver enzyme levels require monitoring
as they can present elevations that rarely necessitate termination of therapy (10).
Drugs can be used as a first line therapy when the general conditions contraindicate
surgery (to alleviate the systemic symptoms due to GH excess) (Figure 4).
- Radiotherapy
When surgery and medical therapy do not lead to hormonal remission, radiotherapy
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is indicated, achieving disease remission in 50% of cases: when the tumour diameter is
less than 2.5 cm, gamma-knife treatment might be preferable to classic radiation therapy
(4).
Essential references
1. Bonneville JF, Bonneville F, Cattin F (2005) Magnetic resonance imaging of pituitary
adenomas. Eur Radiol 15:543-548
2. Dehdashti AR, Ganna A, Karabatsou K, Gentili F (2008) Pure endoscopic endonasal
approach for pituitary adenomas: early surgical results in 200 patients and comparison
with previous microsurgical series. Neurosurgery 62:1006-1015; discussion 1015-1007
3. Fusco A, Zatelli MC, Bianchi A, Cimino V, Tilaro L, Veltri F, Angelini F, Lauriola L,
Vellone V, Doglietto F, Ambrosio MR, Maira G, Giustina A, degli Uberti EC, Pontecorvi
A, De Marinis L (2008) Prognostic significance of the Ki-67 labeling index in growth
hormone-secreting pituitary adenomas. J Clin Endocrinol Metab 93:2746-2750
4. Jagannathan J, Sheehan JP, Pouratian N, Laws ER, Jr., Steiner L, Vance ML (2008)
Gamma knife radiosurgery for acromegaly: outcomes after failed transsphenoidal
surgery. Neurosurgery 62:1262-1269; discussion 1269-1270
5. Laws ER, Vance ML, Thapar K (2000) Pituitary surgery for the management of
acromegaly. Horm Res 53 Suppl 3:71-75
6. Melmed S, Colao A, Barkan A, Molitch M, Grossman AB, Kleinberg D, Clemmons D,
Chanson P, Laws E, Schlechte J, Vance ML, Ho K, Giustina A (2009) Guidelines for
acromegaly management: an update. J Clin Endocrinol Metab 94:1509-1517
7. Nemergut EC, Zuo Z (2006) Airway management in patients with pituitary disease: a
review of 746 patients. J Neurosurg Anesthesiol 18:73-77
8. Scacchi M, Cavagnini F (2006) Acromegaly. Pituitary 9:297-303
9. Unal B, Bademci G, Bilgili YK, Batay F, Avci E (2006) Risky anatomic variations of
sphenoid sinus for surgery. Surg Radiol Anat 28:195-201
10. Vance ML, Laws ER, Jr. (2005) Role of medical therapy in the management of
acromegaly. Neurosurgery 56:877-885; discussion 877-885
Acknowledgements
The Authors would like to thank Dr. Paolo Frassanito for the artists rendering of the
clinical features of acromegaly
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Craniopharyngioma
CHANDRASHEKHAR E DEOPUJARI, MCh, VIKRAM S KARMARKAR, DNB(NS)
Department of Neurosurgery Bombay Hospital Instt of Medical Sciences
Key words: craniopharyngioma, Rathkes pouch, craniopharyngeal duct, surgical
management, raised intracranial pressure, visual disturbance, endocrine
functions
Introduction
Historically, tumour of the Rathkes pouch, adamantinoma, ameloblastoma,
cholestotoma, epithelioma, craniopharyngeal duct tumor, and suprasellar cyst were
some of the names before Cushing (7,9)coined the term craniopharyngioma which is
prevalent today. Craniopharyngiomas have been recognized since the beginning of
modern neurosurgery. With evolving techniques and philosophy in neurosciences, our
management strategies and treatment options for craniopharyngiomas have also evolved.
Pathology
These are histologically benign, usually partly cystic epithelial tumours. The cells of
origin are thought to be ectopic cell rests along the involuted craniopharyngeal duct. The
WHO Classification Of Tumours (2007) classes them as Grade 1 tumours. These
constitute 1.24.6% of all intracranial tumours, are more frequently found in children
in Nigeria and Japan and account for 5-10% of intracranial non-neuroepithelial
neoplasm in children.(34)
There are two varieties- the adamantinomatous and the papillary type. While
adamantinomatous craniopharyngiomas show a bimodal age incidence (5-15 years & 4560 years), the papillary variety is almost always found in adults.
As stated, these tumours arise from the ectodermal epithelial cell remnants of the
craniopharyngeal duct and the Rathkes pouch. Metaplasia of cells from the tooth
primordial cells are said to give rise to the adamantinomatous variety; metaplasia of the
cells derived from buccal mucosa give rise to the papillary variety.
Macroscopically, the adamantinomatous variety is solid-cystic and may be spongy. The
cysts contain dark green-brown fluid resembling machine oil, which is rich in
cholesterol. Secondary changes like calcification, ossification and fibrosis maybe found.
They penetrate the brain and engulf vascular and neural structures. Papillary tumours are
well circumscribed, mainly solid, and are marked by absence of calcification and the
machine oil fluid.
Microscopically, the adamantinomatous type has squamous epithelium arranged in
cords, lobules and irregular trabeculae surrounded by palisaded columnar epithelium.
Cyst cavities contain squamous debris, lined by flattened epithelium. Rosenthal fibres are
often seen at the infiltrative interface of the tumour with the brain. Papillary tumors show
monomorphous masses of well-differentiated squamous epithelium without surface
Craniopharyngioma
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maturation, palisades and wet keratin. There is no calcification seen. Rarely, ciliated
epithelium and goblet cells are seen.
MIB-1 immunoreactivity is high; however no relationship between these indices
and recurrence has been established.(34)
Adamantinomatous tumours show abnormalities involving chromosomes 2, 12 and
also a mutation of the -catenin gene. No mutations of this gene are seen in the
papillary variety.
Pertuiset (33) has elucidated the arterial supply to craniopharyngiomas. The intrasellar tumour gets its supply from cavernous branches of the ICA, while the suprasellar
portion from the anterior cerebral artery, anterior communicating and the posterior
communicating artery. Except for intraventricular extensions or close apposition to the
third ventricle, the posterior circulation does not supply the tumour
Clinical features
Broadly the clinical features of craniopharyngiomas can be due to raised intracranial
tension, endocrinological effects, visual symptoms.
Craniopharyngioma usually grow slowly and clinical features develop insidiously.
Raised intracranial pressure is heralded by headaches, nausea and vomiting,
papilledema either because of the tumour itself or due to hydrocephalus from ventricular
obstruction by the tumour (of the foramen of Monro or aqueduct of Sylvius)
Endocrine functions are normally suppressed viz., hypothyroidism, orthostatic
hypotension, short stature, diabetes insipidus, impotence and amenorrhoea. Rarely
there can be hyperfunction like precocious puberty in children and obesity in adults.
These represent dysfunction of the pituitary-hypothalamus axis.
Visual disturbance. Usually the classic bitemporal hemianopia due to chiasmatic
Compression is seen. Other field defects like homonymous hemianopia, scotoma, optic
atrophy are not uncommon. Retrochiasmal tumours may present only with papilledema
without field defects.
Less commonly chemical meningitis from rupture of cyst contents into the
subarachnoid space, seizures, poor school performance in children or psychiatric
disturbances in adults have been reported.(15)
Radiology
Plain X-rays can show a widened sella with suprasellar calcification. CT imaging of
craniopharyngiomas shows a cystic and solid lesion, which enhances on contrast
injection. There is presence of calcification especially in adamantinomatous
craniopharyngiomas. These are commonly found in the pediatric population. Papillary
craniopharyngiomas are less likely to show calcification(6,46)
MRI is the imaging modality of choice to study craniopharyngiomas. T1 shows the
lesion to be of heterogenous intensity, T2 shows the cystic components to be
hyperintense. The calcifications are hypointense on both T1 and T2. The solid
components enhance on contrast administration. The location of the tumour in its sellar
and suprasellar extensions are studied. Sainte Rose, Kahn et al (35)have classified
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Suprasellar region
hypothalamic involvement on MRI in three grades : Type 0 : no involvement of the
hypothalamus, Type 1 : the hypothalamus is elevated/distorted but visible, Type 2 : the
hypothalamus is involved.
The position of the chiasm in relation to the tumour (prechiasmal or retrochiasmal
tumour) is an important factor to be observed on MRI(2). Classifications like the
Samii classification (36) include divisions like A(anterior/pre-chiasmal), P(posterior
fossa), S(infrasellar), L(lateral/temporal). This would often determine the choice of
approach and the ease with which the tumour can be tackled.
The differential diagnoses include pituitary adenoma, hypothalamic or optic patway
glioma, a Rathkes pouch cyst, an epidermoid. Less commonly a thrombosed aneurysm
or an arachnoid cyst, or pituicytoma may be considered. Purely intraventricular
craniopharyngiomas may occasionally be confused with colloid cyst of the third ventricle
Management options
Treatment is primarily surgical excision. Radiation therapy or radiosurgery and
intra-cavity agents are reserved as adjuvant therapy. Endocrinolgical treatment, especially
replacement therapy, plays an important role.
The history of surgical options for craniopharyngiomas parallels the development of
neurosurgery in general. Many of these approaches to the sellar and suprasellar region
were pioneered during the first half of the last century. Horsley is credited with his middle
cranial fossa approach to lesions in this region (after performing a temporal craniotomy,
with an intra-dural approach, lifting up the temporosphenoidal lobe to reach the
suprasellar space). Krause (24)devised an anterior fossa extra-dural approach to reach
the suprasellar region, opening the dura at the end of the exposure and using a specially
designed knife to excise the tumour. Lewis(27) was amongst the pioneers who described
the tumour pathology accurately in 1910 with a surgical case. McArthur(31), Frazier(11,
12) used the trans-frontal approaches with removal of the orbital roof. Dandy(8)
described Heurers frontolateral approach with a large fronto-lateral craniotomy.
Heurer (18) published his results with this approach in 1920
Concurrently, the extra-cranial approaches were being developed. Schloeffer (37) and
Von Eiselberg (45) developed and used a lateral rhinotomy procedure through the
ethmoid cells, into the sphenoid sinus for approaching sellar lesions. Kanvel(22)
described the infra-nasal route with excision of the septal cartilage and the middle
turbinate bones. A.E Halstead (16) first used Kanavels approach to remove a
craniopharyngioma through the infra-nasal route. Hirsch (19) used a sub-mucosal
resection of the septum to access the sphenoid sinus. Cushing too used the transsphenoidal approach, but abandoned it later because of poor visualization of the
suprasellar pathology. He has reported eighty seven confirmed operated
craniopharyngiomas cases.
Critchley and Ironside (5) from Queens Square, London documented the clinical
findings and pathology in seven patients.. Many other neurosurgeons of the time
published their data for craniopharyngiomas. However, it was becoming clear that this
so called benign tumour was not always so. Frazier, Carpenter (3) suggested surgical
excision followed by radiotherapy in 1937. Ingraham and Matson (20) laid stress on the
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use of corticosteroids in the peri-operative period, in the fifties. Matsons (28, 29, 30)
series of 34 patients without operative mortality was an important landmark in our
understanding of surgical treatment of craniopharyngiomas.
With the advent of the micro-neurosurgical era and improved imaging techniques, the
debates about whether craniopharyngiomas can and should be completely excised
resurfaced. Sweet (38) influenced a generation of neurosurgeons with a strong belief in
radical excision. In the meanwhile, Hardy (17) and Guiot (13) revived and refined the
trans-sphenoidal approaches including for craniopharyngiomas. Laws (25) has probably
the largest series operated through the trans-sphenoidal route. Today, many centers utilize
an endonasal trans-sphenoidal route. Although we have an abundance of therapeutic
options, the quest for the optimum strategy is by no means over.
Today, we can approach these tumours using transcranial microneurosurgical
procedures and the transnasal transsphenoidal endoscopic or trans-ventricular endoscopic
procedures.
Frontal approaches include bi-frontal, unifrontal craniotomies with/without skullbase extensions.
Fronto-lateral approaches like the classic pterional craniotomy and its modifications
have been popularized by Yasargil (46). Smaller fronto-lateral approaches like the supraorbital craniotomy have also been employed. (Fig 1, 2)
Lateral approaches include the temporal (sub-temporal corridor) which was endorsed
by Symon (39, 40, 41). Trans-petrosal approach is useful especially in retro-sellar
variants and have been championed by Hakuba (14) and Al-Mefty (1)
The trans-callosal inter-hemispheric route or endoscopic trans-ventricular
approaches have been used for purely intra-ventricular lesions.(43)(Fig 3)
(a)
(d)
(b)
(e)
(c)
(f)
Fig. 1 Craniopharyngioma operated using the pterional approach and various corridors
including lamina terminalis approach. a, b, c Pre-operative. d, e, f Post-operative
pictures showing complete excision. (Eight year follow up without radiotherapy)
278 Neuro-oncology
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Suprasellar region
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(i)
(j)
Fig. 2 Steps showing supraorbital craniotomy and an illustrative case. (a) extent of bone exposure, (b)
small craniotomy, (c) dural opening, (d) intracranial corridors, (e) endoscopic assistance, (f,g,h)
pre-op images, (i, j) post-op images
Intra-sellar craniopharyngiomas can be approached by the endoscopic transsphenoidal, extended subfrontal or transcranial transsphenoidal approach as described
by Patterson et al (31)(Fig 4) The extended endoscopic trans sphenoidal approach for
suprasellar craniopharyngiomas is well described by Frank et al (10). The endo-nasal
approach involves endonasal endoscopic exposure of the sella through the sphenoid sinus.
The sellar floor is then opened; this is usually thinned out due to the presence of the intrasellar tumour. The dura is opened and the craniopharyngioma is dissected. Based on the
relation of the tumour with infundibulum, Kassam et al(23) have recently classified these
tumours as pre-infundibular, trans-infundibular, post infundibular, and isolated
intrventricular. This classification helps plan extent of the extended trans-sphenoidal
approaches.
The choice of approach depends on the tumour configuration and pattern of growth
and has to individualized from case to case. (table1, 2)
The rates of recurrence with complete excision (15%) versus subtotal removal and
radiotherapy (22%). This has been established in various surgical series (table3)
Craniopharyngioma
(a)
(d)
(b)
Pre-operative MRI
(e)
Post-operative CT Scan
(c)
(f)
(a)
(b)
Pre-operative Imaging
(d)
(c)
(e)
Post-operative
Fig. 4 this patient had a sellar tumour with suprasellar extension. This was
operated by an extended transnasal transsphenoidal approach.
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435
280 Neuro-oncology
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Suprasellar region
Table 1 Various surgical options for different locations of tumour
Craniopharyngioma
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437
bleomycin is then injected daily for six days according to this regime. We have used this
procedure in patients who have developed a cystic recurrence or in patients who have
primarily a cystic tumour with little solid component. (Fig 5)
Interferon alpha has been used as an intra-cystic agent; it is supposed to act by
antagonizing the mitogenic activity of tissues and hematopoietic growth factors.(4)
The side effects of interferon are less compared to bleomycin.
ray emitting agents that have been reported in the management of
craniopharyngioma are phosphorous-32, yttrium-90, Rhenium-186, and Aurum-198. (21,
42)
Post resection radiation therapy is now an accepted option in the treatment algorithm
for craniopharyngioma. Various modalities like the LINAC based techniques, the
Gamma Knife, SRT, IMRT, and proton beam therapy have all been used as adjuvant
therapy. Three to five years of age is considered the cut off for administering radiotherapy
in the pediatric age group(21). When recurrences are seen in the very young, repeat
surgery (technically more demanding) or intracystic adjuvant therapies may be used till
the brain can withstand external beam radiation.
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Suprasellar region
(a)
(d)
(b)
(c)
(e)
Craniopharyngioma
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439
REFERENCES
1. Al-Mefty O, Ayoubi S, Kadri PA: The petrosal approach for the total removal of giant
retrochiasmatic craniopharyngiomas in children. J Neurosurg 106: 87-92, 2007.
2. Bhagwati SN, Deopujari CE, Parulekar GD: Lamina terminalis approach for
retrochiasmal craniopharyngiomas. Childs Nerv Syst 6: 425-429, 1990.
3. Carpenter RC, Chamberlin GW, FrazierCH: The treatment of hypophyseal stalk tumors
by evacuation and irradiation. Am J Roentgenol 38: 162-177-620, 1937
284 Neuro-oncology
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Suprasellar region
4. Cavalheiro S, Dastoli PA, Silva NS, Toledo S, Lederman H, da Silva MC: Use of
interferon alpha in intratumoral chemotherapy for cystic craniopharyngioma. Childs
Nerv Syst 21: 719-724, 2005.
5. Critchley M, Ironside RN: The pituitary adamantinomata. Brain 49(4): 437-481, 1926
6. Curran JG, O'Connor E: Imaging of craniopharyngioma. Childs Nerv Syst 21: 635-639,
2005.
7. Cushing H: Intracranial tumors. Notes upon a series of two thousand verified cases with
surgical mortality percentages pertaining thereto. Thomas, Springfield, IL, 1932
8. Dandy WE: A new hypophysis operationdevised by Dr. G.J. Heurer. Bull Johns
Hopkins Hosp 29: 154-155, 1918
9. DiPatri AJ, Jr., Prabhu V: A history of the treatment of craniopharyngiomas. Childs Nerv
Syst 21: 606-621, 2005.
10. Frank G, Sciarretta V, Calbucci F, Farneti G, Mazzatenta D, Pasquini E: The Endoscopic
Transnasal Transsphenoidal Approach for the Treatment of Cranial Base Chordomas and
Chondrosarcomas. Neurosurgery 59: ONS-50-ONS-57, 2006.
11. Frazier CH, Alpers BJ: Adamantinoma of the craniopharyngeal duct. Arch Neurol
Psychiatry 26(5): 905-967, 1931
12. Frazier CH: An approach to the hypophysis through the anterior cranial fossa. Ann Surg
57: 145-150, 1913
13. Guiot G, Derome P: [Indications for trans-sphenoid approach in neurosurgery. 521
cases]. Ann Med Interne (Paris) 123: 703-712, 1972.
14. Hakuba A, Nishimura S, Inoue Y: Transpetrosal-transtentorial approach and its
application in the therapy of retrochiasmatic craniopharyngiomas. Surg Neurol 24: 405415, 1985.
15. Halac I, Zimmerman D: Endocrine manifestations of craniopharyngioma. Childs Nerv
Syst 21: 640-648, 2005.
16. Halstead AE: Remarks on the operative treatment of tumors of the hypophysis with the
report of two cases operated on by an oro-nasal method. Surg Gynecol Obstet: 494-502,
1910
17. Hardy J, Lalonde JL: [Removal by Trans-Sphenoidal Route of a Giant
Craniopharyngioma.]. Union Med Can 92: 1124-1129, 1963.
18. Heurer GJ: Surgical experiences with an intracranial approach to chiasmal lesions.
Arch Surg 1(2): 368 381, 1920
19. Hirsch O: Die operative Behandlung von Hypophysistumoren nach endonasen
Methoden. Arch Laryngol Rhinol 26: 529-686, 1912
20. Ingraham FD, Matson DD, Mc LR: Cortisone and ACTH as an adjunct to the surgery of
craniopharyngiomas. N Engl J Med 246: 568-571, 1952.
21. Kalapurakal JA: Radiation therapy in the management of pediatric craniopharyngiomas-a review. Childs Nerv Syst 21: 808-816, 2005.
22. Kanavel AB: The removal of tumors of the pituitary body by an infranasal routea
proposed operation with a description of the technique. JAMA 53: 704-707, 1909
23. Kassam AB, Gardner PA, Snyderman CH, Carrau RL, Mintz AH, Prevedello DM:
Expanded endonasal approach, a fully endoscopic transnasal approach for the resection
of midline suprasellar craniopharyngiomas: a new classification based on the
infundibulum. J Neurosurg 108: 715-728, 2008.
24. Krause F: Hirnchirurgie. Die Deutsch Klinik am Eingange des Zwanzigsten Jahrhunderts
in akademischen Vorlesungen 8: 953-1054, 1905
25. Laws ER, Jr.: Transsphenoidal microsurgery in the management of craniopharyngioma.
J Neurosurg 52: 661-666, 1980.
26. Lewis DD: A contribution to the subject of tumors of the hypophysis. JAMA 55: 10021008, 1910
Craniopharyngioma
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Professor of Neurosurgery
Marmara University Medical Center, Head of Department of Neurosurgery;
Acbadem University, School of Medicine, Chief of Division of Pediatric Neurosurgery
Istanbul, Turkey
2
Instructor of Neurosurgery
Marmara University Medical Center, Department of Neurosurgery.
Istanbul, Turkey
Key words: optic pathways, hypothalamus, tumors, neurofibromatosis (NF), NF-1,
optic chiasma, visual loss
INTRODUCTION:
Optic pathways tumors were defined by Wishart initially in 1833 [39]. In a case
report of a 13-year-old girl with proptosis who had been through surgery previously,
tumor tissue was reported as a mass which was located within optic nerve and conducing
to tension on optic nerve sheath. A 40-year time was to pass in order to define optic
pathways tumors in a category exclusive of other orbital tumors [40]. Optic pathway
tumors characterized with surgical and pathological studies in advancing years and
correlation with neurofibromatosis were exposed particularly [41].
EPIDEMIOLOGY
Optic pathway tumors comprise 3-6 of entire childhood brain tumors [2-5]. Datton
[2] reported the average age as 8,8. Only 10% of cases were above 19 at the time of
presentation. As a matter of course, development and intense utilization of modern
neuroradiological workups lower age of diagnosis. No considerable connection between
localization of tumor (tract, chiasma or nerve) and age is available for optic pathway
tumors [2]. Nevertheless, diencephalic syndrome which occurs as a result of early
invasion of hypothalamus (strabismus, loss of weight and developmental retardation)
reveals in cases below the age of 1 [2].
Relationship between optic pathways tumors and neurofibromatosis (NF) is verified
in the middle of last century for the first time [41]. NF-1 incidents which were reported
for patients suffering optic pathways tumors patients are 30% [2,4]. However, the facts
that not all patients with NF-1 are screened for optic pathways tumor and tumors in NF1 cases might be asymptomatic should be considered.
Optic pathway and hypothalamic tumors present different anatomic locations and
different clinical presentation and prognosis relating to that. Thus, detailed and
meticulous classification is required as they are evaluated.
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CLASSIFICATION:
Various optic pathway tumor oriented classifications are notified until today [6-8, 42,
43]. Tumors of optic pathway and hypothalamus present a highly wide morphological
spectrum which reveal different biological manners as from tubular thickening of optic
nerves and chiasma to massive egzophytic lesions. This variety brings difficulties in
observing natural course of disease and analyzing responses to treatment.
Considering anatomic localization, primary classification was prepared by Dodge [6]
in 1958 (Table 1). Tumor was defined in grades of A, B and C in which grade A referred
to tumors which were restricted by a single optic nerve, grade B to chiasma located
tumors independent of nerve involvement, grade C to hypothalamic tumors or tumors
which are posterior through optic pathways.
Table 1 Dodge Classification [6]
Grade
A
B
C
Anatomical Localisation
Confined to one optic nerve
Involvement of chiasma (independent of involvement of optic nerve)
Hypothalamic / Retrochiasmatic optic pathway
Sugita and Kageyama [42] classified the tumors of same group for their clinical,
pathological and patient age (Table 2). Tumors are classified in two as infantile type and
childhood type according to patient age. Infantile type tumors are respectively
large invading hypothalamus at early phase causing serious visual loss, intracranial
pressure increase and hypothalamic function disorder; in consequence, these tumors have
malignant prognosis.
Table 2 Sugita and Kageyama classification [42]
Patient age
Infantile type
Childhood type
Clinic
Hypotalamic invasion
Severe visual loss
Increased intracranial pressure
Hipotalamic dysfunction
Involvement of optic nerve / chiasma
More benign course
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Table 3 Yasargil Classification [43]
Type
Type I
Anatomical Localisation
Type IA
Type IB
Type II
Type III
Type IIIA
Type IIIB
Retrobulber (intraorbital)
Retrobulber (intraforaminal)
Optic nerve involvement
Unilateral chiasmatic
Bilateral chiasmatic
The classification of Ahn et al. [9] also considers anatomic localization. Tumors are in
two main groups as anterior and posterior located (Table 4). According to this; anterior
located optic pathway gliomas are divided into three groups as intraorbital nerve
involvement, intraorbital optic nerve + optic chiasma involvement and intracranial
optic nerve + optic chiasma involvement. Posterior located optic pathway gliomas are also
divided into three sub-groups as optic chiasma + hypothalamus involvement, optic
chiasma + optic tractus involvement, optic chiasma + hypothalamus involvement,
optic chiasma + hypothalamus and optic tractus involvement.
Table 4 Ahn et al. classification [9]
Type
Anterior localization
Posterior localization
Chiasma + Hypotalamus
Chiasma + Optic tractus
Chiasma + Hypotalamus ve optik tractus
McCullough and Epstein [8] prepared a new classification which depends upon
standard oncologic terminology (T grade) and bases visual (V grade) function of
patient by anatomic grading. Anatomic localization of tumor (Table 5a) is defined
considering posterior lengthening of that, T1 defines optic nerve involvement, T2
defines involvement of both optic nerves, T3 defines optic chiasma involvement and T4
defines hypothalamus/thalamus involvement. Visual function (Table 5b) is graded
from regular visual to bilateral blindness as from V0 to V4. No practical good of
including neurological and endocrinal deficits in grading system was observed in this
classification.
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Stage
T1
T2
T3
T4
Localization of tumor
Unilateral optic nerve (intraorbital or intracranial)
Bilateral optic nerves
Chiasma
Hypotalamus / thalamus
Stage
V0
V1
V2
V3
V4
Visual function
Normal
Distorted, one eye or abnormal VEP
Distorted, both eyes or blindness in one eye
Blindness, in one eye; distortion in one eye and visual field defect
in one eye
Blindness, bilateral
CLINIC
Clinic of patient alters according to localization of tumor:
I. Intraorbital (pre-chiasmatic) located gliomas:
Progressive visual loss and proptosis [10, 11] are primary clinical findings of
intraorbital located tumors (Fig. 1). The eye in which tumor is located is
usually downward and laterally directed. Nystagmus and strabismus may be the
primary findings in infantile.
II. Chiasmatic Gliomas:
Chiasmatic gliomas have visual acuity reduction and bilateral visual area
defect coupling. Endocrinological disorder and hydrocephalus are quite rare
(Fig. 2).
III. Egzophytic chiasmatic hypothalamic gliomas:
Visual loss, endocrine and hypothalamic dysfunction and symptoms related to
Fig. 1
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Suprasellar region
Fig. 2
Fig. 3
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DIAGNOSIS
Current method of choice for cases which are clinically considered to have optic
pathways and hypothalamic tumor would be magnetic resonance (MR). Yet other
methods are to be mentioned briefly.
Extension of optic canals which occur in direct graphies over 2 millimeters or 25-30%
and J shaped sella turcica optic nerve involvement are observed in 65-85% of cases [14].
Computed tomography examination may reveal clean infinite mass of optic nerve
while tumor is restricted by optic nerves. Determination of detailed anatomic structure
of mass would be hard in chiasmatic tumors. Within rare occasions, suprasellar
lengthening lesions may present calcification.
Today MR is the effective diagnostic method. Iso hypointensity in T1 weighted
inspections, hyperintensity in T2 weighted inspections, homogenous enhancement of
lesions after contrast material injection are typical findings of MR in these cases.
According to anatomic localization, some variations may occur in MR findings.
A. prechiasma optic nervegliomas present fusiform extension in orbita and optic
canal. In addition, no chiasma involvement is observed. Particularly in T2
weighted analysis, signal intensity presents no increase in chiasma or optic
tracts. Bilateral involvement in neurofibromatosis may occur.
B. Along with variable lengthening to optic tracts and optic nerves, diffuse
extension of optic chiasma occurs in chiasma gliomas. Especially contrast T1 and
T2 weighted MR analysis is quite contributive defining involvement of both
tumors and other close structures. MR findings are pathognomonic while
neurofibromatosis exists. A hyperintensity with respectively lower intensity
around it inspected during the inspection of T1, double intensity or pseudo-BOS
signal feature is characteristic findings for NF1 [2,15]. In addition, infiltrative
lesions are much common in patients with NF1 in comparison to those without
NF1 [3]. Germ cell tumors, sarcoidosis and suprasellar dermoid cysts should
appear in distinctive diagnosis in neurofibromatosis absence.
C. Exophytic chiasma-hypothalamic gliomas present wide lengthening to suprasellarparasellar area and third ventricle. Origin of tumor should be determined. It may
be optic nerve or chiasma. These tumors usually are diffuse or patchy. Tumors
in infantile are usually accompanied with ex-tumor arachnoid cysts located right
beside tumor which present lengthening to silvian fissure. Since dissemination
may occur at the moment of diagnosis exclusively in children below 5, entire
neural axis should be included in monitoring.
Routine biopsy no longer takes place. Biopsy is recommended only for extraordinary
clinical and radiological cases today. [10].
PATHOLOGY
Optic pathways and hypothalamic tumors are often low graded gliomas. Considerable
parts of them consist of pilocytic astrocytoma [2]. Fibrils are rarely observed. Besides,
pilocytic astrocytoma topic defines a new sub-group [16]. Rosenthal fibers are not
included in these tumors, eosinophilia granuloma particles are observed rather less. 14%
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of patients with optic pathways tumor which received pilocytic astrocytoma diagnosis
have CSF dissemination at presentation. These cases are present at very early ages (18
months in average) and tumor frequently presents an aggressive manner [16].
TREATMENT
From a historical view radiation appears to be the primary treatment of optic
pathways tumors. However, in consequence of post-radiation development of cognitive
and endocrine disorders, secondary tumor development and moyamoya disease, this
method became controversial [17, 18]. Furthermore, development of microsurgical
methods, new regulations of chemotherapy protocols and acquisition of natural course
of disease caused development of alternative treatments due to lesion type, age and clinical
condition of patient.
Table 6 presents treatment algorithm of optic pathways and hypothalamic tumors
considering Dodge classification due to types of tumors.
Type A: Treatment of single optic nerve involvement forms according to visual
function. Cases of entire visual loss and with tumors advancing, surgery
would be the treatment. Recurrence condition brings forth the
chemotherapy as the second option. For the cases which patients still have
visual function to manage daily life, radiological follow-up is
recommended. Chemotherapy and/or radiation treatment (conventional
or focal radition) should be performed if disease presents progression.
Type B: Chemotherapy is the first option for diffuse chiasma involvement cases.
Radiotherapy option should be in mind for any progression after
chemotherapy occurs.
Type C: Treatment of exophytic chiasmatic- hypothalamic optic pathway tumors,
age and diencephalon findings is closely related. Cases above the age of
one and without diencephalic findings require surgical treatment.
Chemotherapy/radiotherapy should be performed for any progression of
disease postoperatively. Immediate shunt insertion and septostomy may
be required for hydrocephalus.
Surgery
Since total tumor resection in T1 tumors cause blindness, surgery should be performed
to patients which have visual function limited with single optic nerve and to those
with no visual function [10]. This surgical procedure requires extradural and intradural
combined approach. Pterional or frontotemporal craniotomy is performed. Upper
orbita and superior optic foramen are excised. Then, periorbita is opened and intraconal
part is revealed. Optic nerve is cut where it penetrates the bulbus and traced through
posterior where inside of optic foramen is revealed. If a tumor exists on intracranial
component of optic nerve, surgery is performed as intradural and optic nerve is cut where
it appears morphologically normal. Determination of whether tumor cell exists on
proximal end is significant during the pathological evaluation of the tissue.
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Suprasellar region
Fig. 4
Fig. 5
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451
Interhemispheric transcallosal or pterional approaches are preferred in chiasmatichypothalamic tumors. Ideal approach to cases which are located in midline, filling the
whole III. ventricle and causing hydrocephalus is interhemispheric approach (Fig. 4). On
the other hand, for cases of asymmetric localization, pterional approach should be
preferred (Fig. 5).
Case presentation of spontaneous regression of tumor in patients who have received
no other treatment than surgical excision of optic pathways tumors or post-operative
term after biopsy is also reported [3, 4, 19].
Patients with neurofibromatosis (NF) comprise the sub-group of optic pathways
tumor patients. Local disease in these cases is rarely observed. In addition, these patients
present tendency to recurrence [20 21]. Failure ratio in patients with neurofibromatosis
which are excised totally is found twice in comparison to those without neurofibromatosis
[4, 20, 21]. These findings do not reveal malignant course, but show inconvenience for
surgery.
Regardless of having NF, 92% survival ratio of patients who had only optic nerve
involvement after complete surgical resection within 15 years is reported [22]. Survival
ratio of lesions located posterior of chiasma within 10 years of relapse-free term is
41% which is significantly lower [22]. Distinction between neuropsychological deficit
which is constituted due to surgery and deficit which is constituted due to only tumor is
quite hard, in fact since that may not be possible, postoperative neurocognitive evaluation
and results may be evaluated differently [23].
Chemotherapy
Even though different chemotherapeutic agents are revealed to be effective on low
graded gliomas, Packer regime is still the most frequently used chemotherapy regime [24,
25]. 10 weeks of simultaneous utilization of carboplatin and vincristin which is followed
by 48 weeks carboplatin / vincristin continuation of treatment protocol is defined in
induction phase. As a consequence of this regime, 75,3% for 2 years, 68% per year, and
50% for 5 years time survival ratios are notified; furthermore, treatment ratio for
children below age of 5 is reported to be much better.
Consequently, protocols which are defined for treatment of low graded gliomas in
literature are also emphasized as applicable to optic pathways tumors [26].
Radiotherapy
Role of radiotherapy (RT) in treatment of optic pathways and hypothalamic tumors
was emphasized by Taveras et al. [27] in 1956. However, radiotherapy is not
recommended for patients below age of 5 today [28, 29]. There are publishes available
notifying no additional benefits of radiotherapy in comparison to surgical intervention
or follow-up in protection of visual, 10 years progression of radiotherapy and long-term
survival [2, 22]. Common opinion today is to perform chemotherapy to patients below
5 as primary treatment option. Although there has been no consensus achieved on
treatment to perform in patients between 5 and 10, an agreement to perform 50-54 Gy
irradiation each one to be between 160-200 cGy in patients over 10 is available [30, 31].
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External beam radiotherapy is still the most frequently used radiotherapy approach;
in addition, new technologies as stereotactic radiotherapy and proton beam radiotherapy
are also used in recent years [14, 15]. Stereotactic radiotherapy provides 79% survival in
5 years time without cognitive or endocrinologic adverse effects which traditional
external beam radiotherapy frequently causes [10, 15]. Proton beam radiotherapy has
been found to be more interesting within recent years. Even though it is performed in a
few centers, it applies high dose of beam into lesion and loses its affect before the beam
reaches close, healthy tissue. This feature may be considered as an advantage. It is
notified that in little cases patients tolerate its beam fine, nevertheless, supremacy on
standard cases has not been proved yet.
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CONCLUSION
Optic pathway and hypothalamic tumors are lesions which may present various
clinicopathologic manners. Current tendency in treatment is to perform CT and surgery
initially and save RT for recurrence and progressive diseases. RT presents fine results when
it is applicable. However, counter to potential adverse effects close follow-up is required.
REFERENCES
1. Parsons JH: The pathology of the eye. London,, Hodder and Stoughton, 1904.
2. Dutton JJ: Gliomas of the anterior visual pathway. Surv Ophthalmol 1994;38:427-452.
3. Hoffman HJ, Humphreys RP, Drake JM, Rutka JT, Becker LE, Jenkin D, Greenberg M:
Optic pathway/hypothalamic gliomas: A dilemma in management. Pediatr Neurosurg
1993;19:186-195.
4. Jahraus CD, Tarbell NJ: Optic pathway gliomas. Pediatr Blood Cancer 2006;46:586-596.
5. Tao ML, Barnes PD, Billett AL, Leong T, Shrieve DC, Scott RM, Tarbell NJ: Childhood
optic chiasm gliomas: Radiographic response following radiotherapy and long-term
clinical outcome. Int J Radiat Oncol Biol Phys 1997;39:579-587.
6. Dodge HW, Jr., Love JG, Craig WM, Dockerty MB, Kearns TP, Holman CB, Hayles AB:
Gliomas of the optic nerves. AMA Arch Neurol Psychiatry 1958;79:607-621.
7. Fletcher WA, Imes RK, Hoyt WF: Chiasmal gliomas: Appearance and long-term
changes demonstrated by computerized tomography. J Neurosurg 1986;65:154-159.
8. McCullough DC, Epstein F: Optic pathway tumors. A review with proposals for clinical
staging. Cancer 1985;56:1789-1791.
9. Ahn Y, Cho BK, Kim SK, Chung YN, Lee CS, Kim IH, Yang SW, Kim HS, Kim HJ, Jung
HW, Wang KC: Optic pathway glioma: Outcome and prognostic factors in a surgical
series. Childs Nerv Syst 2006;22:1136-1142.
10. Binning MJ, Liu JK, Kestle JR, Brockmeyer DL, Walker ML: Optic pathway gliomas: A
review. Neurosurg Focus 2007;23:E2.
11. Rodriguez LA, Edwards MS, Levin VA: Management of hypothalamic gliomas in
children: An analysis of 33 cases. Neurosurgery 1990;26:242-246; discussion 246-247.
12. Ng YT, North KN: Visual-evoked potentials in the assessment of optic gliomas. Pediatr
Neurol 2001;24:44-48.
13. Listernick R, Louis DN, Packer RJ, Gutmann DH: Optic pathway gliomas in children
with neurofibromatosis 1: Consensus statement from the nf1 optic pathway glioma task
force. Ann Neurol 1997;41:143-149.
14. Fuss M, Hug EB, Schaefer RA, Nevinny-Stickel M, Miller DW, Slater JM, Slater JD:
360 Neuro-oncology
454
Suprasellar region
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
Proton radiation therapy (prt) for pediatric optic pathway gliomas: Comparison with 3d
planned conventional photons and a standard photon technique. Int J Radiat Oncol Biol
Phys 1999;45:1117-1126.
Pepin SM, Lessell S: Anterior visual pathway gliomas: The last 30 years. Semin
Ophthalmol 2006;21:117-124.
Komotar RJ, Burger PC, Carson BS, Brem H, Olivi A, Goldthwaite PT, Tihan T:
Pilocytic and pilomyxoid hypothalamic/chiasmatic astrocytomas. Neurosurgery
2004;54:72-79; discussion 79-80.
Desai SS, Paulino AC, Mai WY, Teh BS: Radiation-induced moyamoya syndrome. Int
J Radiat Oncol Biol Phys 2006;65:1222-1227.
Sharif S, Ferner R, Birch JM, Gillespie JE, Gattamaneni HR, Baser ME, Evans DG:
Second primary tumors in neurofibromatosis 1 patients treated for optic glioma:
Substantial risks after radiotherapy. J Clin Oncol 2006;24:2570-2575.
Zizka J, Elias P, Jakubec J: Spontaneous regression of low-grade astrocytomas: An
underrecognized condition? Eur Radiol 2001;11:2638-2640.
Alvord EC, Jr., Lofton S: Gliomas of the optic nerve or chiasm. Outcome by patients' age,
tumor site, and treatment. J Neurosurg 1988;68:85-98.
Deliganis AV, Geyer JR, Berger MS: Prognostic significance of type 1 neurofibromatosis
(von recklinghausen disease) in childhood optic glioma. Neurosurgery 1996;38:11141118; discussion 1118-1119.
Jenkin D, Angyalfi S, Becker L, Berry M, Buncic R, Chan H, Doherty M, Drake J,
Greenberg M, Hendrick B, et al.: Optic glioma in children: Surveillance, resection, or
irradiation? Int J Radiat Oncol Biol Phys 1993;25:215-225.
Carpentieri SC, Waber DP, Pomeroy SL, Scott RM, Goumnerova LC, Kieran MW, Billett
AL, Tarbell NJ: Neuropsychological functioning after surgery in children treated for brain
tumor. Neurosurgery 2003;52:1348-1356; discussion 1356-1347.
Huncharek M, Wheeler L, McGarry R, Geschwind JF: Chemotherapy response rates in
recurrent/progressive pediatric glioma; results of a systematic review. Anticancer Res
1999;19:3569-3574.
Packer RJ, Ater J, Allen J, Phillips P, Geyer R, Nicholson HS, Jakacki R, Kurczynski E,
Needle M, Finlay J, Reaman G, Boyett JM: Carboplatin and vincristine chemotherapy for
children with newly diagnosed progressive low-grade gliomas. J Neurosurg 1997;86:747754.
Reddy AT, Packer RJ: Chemotherapy for low-grade gliomas. Childs Nerv Syst
1999;15:506-513.
Taveras JM, Mount LA, Wood EH: The value of radiation therapy in the management
of glioma of the optic nerves and chiasm. Radiology 1956;66:518-528.
Listernick R, Ferner RE, Liu GT, Gutmann DH: Optic pathway gliomas in
neurofibromatosis-1: Controversies and recommendations. Ann Neurol 2007;61:189198.
Walker D: Recent advances in optic nerve glioma with a focus on the young patient. Curr
Opin Neurol 2003;16:657-664.
Erkal HS, Serin M, Cakmak A: Management of optic pathway and chiasmatichypothalamic gliomas in children with radiation therapy. Radiother Oncol 1997;45:1115.
Horwich A, Bloom HJ: Optic gliomas: Radiation therapy and prognosis. Int J Radiat
Oncol Biol Phys 1985;11:1067-1079.
Hoffman HJ, Soloniuk DS, Humphreys RP, Drake JM, Becker LE, De Lima BO, Piatt JH,
Jr.: Management and outcome of low-grade astrocytomas of the midline in children: A
retrospective review. Neurosurgery 1993;33:964-971.
Janss AJ, Grundy R, Cnaan A, Savino PJ, Packer RJ, Zackai EH, Goldwein JW, Sutton LN,
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
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Surgery,
Complication,
The transsphenoidal midline route represents the standard approach to the pituitary
and sellar area and is used for more than 95% of surgical indications in this region. The
versatility of the transsphenoidal approach for a variety of lesions in the sellar area is
based on a long history of successful outcomes. It is the least traumatic route to the sella
turcica, avoiding brain retraction, and provides excellent visualization of the pituitary
gland and lesions related to it. It is usually more effective and offers lower morbidity
and mortality when compared with transcranial procedures.1 As Edward Laws Jr.
rightly wrote in 2005, Transphenoidal approach is the result of evolutionary process
rather than revolutionary one. It has involved innovative thoughts and perseverance
of multiple generations of neurosurgical pioneers, advances in medical sciences and
surgical techniques, and technological progress, all of which continues to develop
today. 2
TRANSCRANIAL APPROACH
Transcranial approach requires craniotomy and retraction of the frontal lobes of
the brain. It may give sub-optimal exposure of inferior and posterior aspects of the
tumor, but it is difficult to distinguish a normal gland from the tumor from a distal
perspective.
Microscopic Transphenoidal approach is the standard operation for most pituitary
adenomas in the majority of centers. However, most neurosurgeons are now preferring
to use the Endoscopic Transsphenoidal approach instead of the Microscopic approach
due to better results, less morbidity and mortality and more rapid recovery.
457
INSTRUMENTS
Straight instruments are preferable as they can be inserted close to the endoscope
along its axis. The instruments are equipped with differently angled tips so that the
surgeon can manage all areas visible as a result of the wider view afforded by the
endoscope. Soft tissue debrider and a narrow skull base drill is very helpful for the
nasal and sphenoid stage of surgery.
SELECTION OF PATIENT
Switch progressively from sub labial to endonasal microsurgical procedure followed
by endoscopic assisted procedure. Once comfortable with endoscope in the nose, one
could remove speculum and work with the scope only. This can be done after a few
cases. The best tumor to operate in the beginning is a non-functioning lesion with a
well pneumatized sphenoid, with normal nasal anatomy and carotids lying at least 1.5
cm away from each other. The worst is an Acromegallic patient or a presellar type of
sphenoid sinus with tricky anatomy. (FIG 1)
PLANNING
Planning before an endoscopic pituitary surgery is vital. Always study images
carefully for carotid position and identify vascular flow voids on MRI. In acromegalic
patients, attention must be paid to the preoperative MRI to properly identify the rare
but dangerous condition of kissing carotid arteries that are in contact in the midline. 3
In acromegaly, the bone is thicker, blood vessels are larger, carotids more tortuous,
and anesthesia and intubation problematic. When operating on microadenomas,
attention should be paid to choosing the nostril that gives a straight approach to the
side of the sella that is of interest, usually the contralateral nostril, when the tumor
is laterally located close to the cavernous sinus. This allows better visual control and
easier tumor manipulation, ensuring a more feasible and complete resection.
In macroadenomas, MRI should be studied thoroughly for shape, especially
dumbbell with waist, lateral and suprasellar extension or into sphenoid. Consistency
of giant invasive adenoma can be predicted hard with tumor being hypointense on T2
weighted MRI. (FIG 2)
Fig. 2 (a)
Fig. 2 (b)
459
PROCEDURE
Patient is given general anesthesia with orotracheal intubation. A throat pack
should be applied with care, to avoid trickling of blood distally. Postoperative vomiting
secondary to blood in the stomach may cause rise in ICP and subsequently nasal
bleeding or CSF leakage.
Various positions for transsphenoidal approach have been applied with advantages
of their own. Whichever position one is comfortable with should be used. We position
our patients in supine with the trunk elevated 10 degrees and head turned 10 degrees
towards the surgeon. The inclination of the head in the vertical plane varies with the
anatomy of the lesion. If the lesion is primarily in the sphenoid sinus or the clivus, the
head is positioned slightly flexed. Lesions that extend toward the suprasellar region or
in the planum sphenoidale, the head of the patient is left in a neutral position or even
hyperextended. This is to avoid the endoscope being too close to the chest as it may
cause instruments or scope hitting the chest wall.
The surgeon should have close collaboration with the anesthesiologist. Slight
controlled hypotension and excellent analgesia minimize mucosal bleeding. This
avoids recurrent irrigation or lens cleaning, leading to quicker surgery with minimal
side effects.
THE ENDOSCOPE
Avoid quick movements in proximity to surgical target. Execute in and out
movements inside the nasal cavity to get a sense of depth and to fix surgical landmarks.
Clean endoscope lens through irrigation sheath and work bimanually during large
lesion removal. Holder can be used in cases where assistant is unavailable or surgeon is
comfortable with the holder.
AVOID BLEEDING
Before making an incision in the dura, puncture with 25-gauge lumbar puncture
needle or use Dopplar to confirm absence of vascular structure. It is important to
remember that sellar dura has two layers and dissection between them will cause
bleeding. It can be profuse in Microadenomas and in patients with Cushings Disease.
Intercavernous sinus bisects the sella anteriorly. It can bleed profusely and can be
controlled with clips after the sinus is skeletonized by incising the dura on both sides
of the sinus.
Nasoseptal complications are rare and include olfactory problems and delayed
hemorrhage4. These can be avoided by knowing the anatomy and caring for olfactory
tracts. Where the septal flap is not required, adequate coagulation of septal or
sphenopaltine artery is essential to avoid delayed nasal bleed. Sphenoid sinusitis is
seen rarely too and should be suspected in peresistant headache following surgery. The
treatment is generally medical. 4
For large tumors, both middle turbinates may be lateralized to provide adequate
working room. Force applied too close to the attachment of the middle turbinate to the
FLAP
Extended approaches and large tumors had significant risk of CSF fistula and
meningitis. Hadads flap reduces the risk significantly.6 The flap is planned before
surgery and is designed according to size and shape of the anticipated defect. It is best
to overestimate the flap and then trim, if needed. Xylocaine with adrenaline, 1:100000
is injected into the anterior portion of the nasal septum. Extended length angled
Colorado tipped Bovie cautery set to 10 is used to make two parallel incisions following
the sagittal plane of the septum, one over the maxillary crest and the other 1 to 2 cm
below the most superior aspect of the septum to preserve the olfactory epithelium.
These incisions are joined anteriorly by a vertical incision. At the posterior septum, the
superior incision is extended laterally and with an inferior slant over the rostrum of the
sphenoid sinus crossing it horizontally at the level of the natural ostium. The inferior
incision is extended superiorly along the free posterior edge of the nasal septum and
461
then laterally to cross the posterior choana below the floor of the sphenoid sinus.
Elevation starts anteriorly with a Cottle dissector or Freer and the septal incisions may
be completed with scissors. Elevation of the flap from the anterior face of the sphenoid
sinus is completed with preservation of a posterolateral neurovascular pedicle. (FIG3)
Fig. 3 Black dotted line showing schematic vascularized flap on septal artery. A-Sphenoid Ostium, BNasospetal Artery, C- Middle Turbinate, D- Spheno-ethmoidal recess, EChoana, F-Midline Septum.
It is important to complete all incisions before the elevation of the flap because it
becomes difficult to orient the tissue and to hold it with mild tension, once it has been
elevated. Elevation of the flap is completed leaving it pedicled on the posterior septal
neurovascular bundle. It is placed into the choana or nasopharynx.
Fig. 4 Sphenoid rectangular anatomy after wide sphenoid opening showing mimicking fetal face
Sometimes, the anatomy may not be clear but at least the planum, clivus and carotid
protuberance can safely identify the sellar floor. The principle of this exposure is to
create a single large rectangular cavity within the sphenoid sinus. This allows for the
placement of the endoscope close to the target, which is essential for visualization by
allowing for the delivery of divergent light close to the target.
WARNING
Initial removal of central and superior parts of macroadenoma will deliver redundant
diaphragm into operative field, obscuring the remaining tumor. This makes further
resection difficult and also increases the chance of CSF leak, when trying to remove the
tumor by pushing the diaphragm. In large dumbbell adenomas, care should be taken in
trying to take the tumor out from the small waist of the dumbbell as it can cause CSF
leak or bleeding into subarachnoid space.
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The bilateral endonasal approach can facilitate the removal of large macroadenomas
with both supra- and parasellar extensions. In these cases, because the instruments
introduced through one nostril have a slightly medial angulation, their working angle
can effectively reach the contralateral, suprasellar, and parasellar portions of the lesion 8.
This approach may also be used when the patient has narrow nasal cavities or anatomic
variations, making progression to the sella difficult. In such cases, the simultaneous use
of the other nostril can be advantageous, with minimal additional trauma.
Suprasellar complications include CSF fistula, meningitis, hemorrhage into the tumor
bed or in subarachnoid space, if the arachnoid is taken with aggressive pulling of tumor
without vision in dumbbell shaped macroadenoma4. Surgery with direct endoscopic
vision is a must and no instrument should be used blindly.
SELLA REPAIR
Repair of the sella is performed with the purpose of creating a protective barrier,
reducing the dead space and preventing the chiasm from descent into the sellar cavity.
Overpacking of the sella must be avoided to prevent compression of the optic system.
HEMOSTASIS
Bleeding prolongs the operative time and identifying the tumor and normal pituitary
gland becomes very difficult. In some cases the surgery is prematurely aborted due to
uncertain view. Warm water irrigation and wash is helpful in reducing the bleeding. Ice
cold, Pistol (Kassam) Bipolar cautery with curved and different angle is essential for
safe and clean surgery. Bone wax with patties could be used to stop unusual sinusoids
bleeding. Xylocaine with Adrenaline packing is used with ribbon gauze or large cotton
patties at start of surgery and left for 10 minutes to avoid mucosal bleeding. Patties
soaked in same are used for vasoconstriction to push the middle turbinate laterally
with Mitchels dissector. Gel foam, Avitene and surgicell sandwiches may be used for
bleeding from sphenoid mucosa or mucosa around the sphenoid and also in tumor bed
in large Macroadenomas.
Cottonoid and patience is the mainstay of haemostasis whereas FloSeal (Fusion
Medical technologies) could be used for major bleeds. Adrenalin soaked Cottonoid is
not used once arachnoid is breached or with intradural pathology.
The nasopharynx, oropharynx and stomach are then suctioned. Ordinarily, the nose is
not packed. We use temporary nasal packing if a large CSF leak occurs and the sphenoid
sinus has been packed with fat, particularly if we believe that the sphenoidotomy is too
large to keep the fat in place. The packing is removed on the second postoperative day.
We do not routinely use lumbar drain, a bladder catheter, or central lines.
Postoperatively, patients receive oral decongestant agents for 2 weeks, saline nasal
sprays hourly during waking hours, and oral antibiotic agents for 5 days.
ADVANTAGES
The advantages and limitations of transsphenoidal endoscopy should be
comprehensively considered.1 Endoscopy offers a very special and wide visualization,
close to the target and inside the anatomy. The panoramic view provided by the
endoscope, allowing the identification of all the landmarks around the sella during the
entire procedure, minimizes the chance of an inaccurate orientation. It is, therefore,
possible to avoid the use of fluoroscopy, which reduces the amount of radiation to the
patient and the surgical team during the procedure. The avoidance of the speculum
allows wide movements of the instruments in all directions, it is not limited by the
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rigid blades, it reduces facial swelling and nasal pain caused by the overspreading of
the speculum, often needed to widen the surgical corridor. The endonasal approach
allows for the improvement of breathing difficulties, headache, and dryness of the oral
mucosa caused by the absence of postoperative nasal packing.11 Messerer showed that
endoscopic surgery has better results than Microscopic surgery in 164 patients with
better resection rate and endocrinological outcome.12 We are all seeing the same trend
and it may well be because of our better understanding of anatomy and visualization
with newer better instrumentation.
The introduction of endoscopic techniques has produced a stone-in-the-pond effect,
influencing the relatively peaceful neurosurgical environment. 1
The brilliant increased vision of the surgical target offered by the endoscope can allow
more effective removal of the lesion, followed by superior clinical results and a reduction
in complications.
The ideal skull base surgeon understands oncological principles, is familiar with
principles of cerebrovascular surgery, is able to perform both open and endoscopic
approaches, can offer patients the best approach for their pathology, is able to choose
the best reconstruction for the defect and is prepared to deal with emergencies that
require a transition from an endoscopic to an open approach. 14
Thoroughly understanding pituitary endocrinology, selection of right patients
for surgery, managing pre and postoperative care and learning to make appropriate
decisions during surgery is essential. It is important to train properly and learn from
experience of other people to avoid making the same mistakes again. Guidelines should
be followed when performing such surgery. One may start with simple surgery and
after experience go on to do extended approaches and reconstruction. One must read,
teach, share knowledge, learn from cadaver dissection, improve endoscopic skills and
carefully plan each surgery. Adequate endoscopes and proper instrumentation for
specific procedures are essential. A trained team working in coordination can produce
good results in this new horizon.
REFERENCES:
1. Enrico de Divitiis, M.D.: ENDOSCOPIC TRANSSPHENOIDAL SURGERY:STONEINTHE-POND EFFECT. Neurosurgery 59:512-520, 2006
2. Adam S. Kanter, Aaron S. Dumont, Ashok R. Asthagiri, Rod J. Oskouian, John A.
Jane Jr., And Edward R. Laws Jr.: The transsphenoidal approach. Neurosurg Focus 18
(4):E6, 2005
3. Luigi M. Cavallo, Mateus Dal Fabbro, HasanJalaloddin,Andrea Messina, Isabella
Esposito, Felice Esposito, Enrico de Divitiis, Paolo Cappabianca: Endoscopic
endonasaltranssphenoidal surgery.Before scrubbing in: tips and tricks. Surgical
Neurology 67 (2007) 342347
4. Paolo Cappabianca, Luigi Maria Cavallo, AnnamariaColao, And Enrico De Divitiis:
Surgical complications associated with the endoscopic endonasaltranssphenoidal
approach for pituitary adenomas. J Neurosurg 97:293298, 2002
5. Paolo Cappabianca, Luigi Maria Cavallo, And Enrico De Divitiis: Endoscopic
EndonasalTranssphenoidal Surgery. Neurosurgery 55:933-941, 2004