Most pituitary adenomas produce elevated serum levels of one or more
anterior pituitary hormones; these include adenomas secreting growth
hormone (GH), adrenocorticotropic hormone (ACTH), prolactin,
follicle-stimulating hormone (FSH), and thyroid-stimulating hormone
(TSH). These are called secretory pituitary adenomas. Nonsecretory
pituitary adenomas constitute a loosely defined group that includes the
pituitary tumors that remain when the tumors noted above are removed
from consideration; they are associated with normal or low serum levels
of GH, ACTH, prolactin (usually, but see below), FSH, and TSH. They are
also called nonfunctional, clinically nonfunctioning, silent, and
endocrine-inactive adenomas, and generally correspond to the pathologic
diagnoses of null-cell adenoma and oncocytoma.
Our
growing understanding of pituitary pathophysiology has led to a steady
diminution in the number of pituitary adenomas considered to be
nonsecretory. In the nineteenth century, Pierre Marie and Paul Broca
described acromegaly and then related it to a pituitary mass. In the
early part of the twentieth century, Cushing associated hypersecretion
of ACTH with a basophilic pituitary adenoma. Hyperprolactinemia was
identified after the development of immunoassays in the latter half of
the twentieth century. Now tumors with clinically assayable hypersecretion of the glycoprotein hormones TSH, FSH, and luteinizing
hormone (LH) or their subunits have been separated as well. The
separation of these specific hypersecretory adenomas is a tribute to the
power of modern endocrinology and the pivotal role of immunoassay
techniques in understanding pituitary adenomas. One importance of
finding a secretory product in serum is that it allows a hormonal test
of tumour activity for follow-up.
Nonsecretory tumors comprise about 40 percent of adenomas in most
surgical series. In imaging, they may resemble other lesions around
the pituitary such as craniopharyngiomas, meningiomas, and intrasellar
cysts, as discussed below; the correct diagnosis may be made only at
surgery.
Clinical
Diagnosis
There are four common clinical
presentations for a non secretory pituitary adenoma: visual blurring,
headache, loss of libido, or absence
of symptoms. Tumors may be surprisingly large for the relatively mild
symptoms they produce.
Visual
symptoms are found in 60 to 70 percent of cases, usually as loss of the
temporal field in one or both eyes, loss of visual acuity, or vague
blurring of vision. The early stages of peripheral
field loss may not be noticed by the patient, and there may be rather
substantial deficits on neuroophthalmologic testing at the time of
tumour diagnosis. More common than field loss is non-specific blurring of
vision, which may bother the patient with reading. This may not be
detected on formal testing but is a definite and common symptom related
to visual pathway compression. Diplopia or evident extraocular muscle
weakness is rare, and should raise the possibility of a metastatic
tumour
or pituitary apoplexy rather than a routine non secretory pituitary
adenoma no matter how large.
Headache
is found in about 40 percent of patients. It is often non-specific
and is felt primarily in the vertex as a dull ache that is constant and
does not vary with position or time of day. Most often it is not
incapacitating but is a definite symptomatic change for the patient. A
rare but important headache syndrome in nonfunctioning adenomas is
found in pituitary apoplexy. This presents with severe, sudden headache
accompanied by neck stiffness and prostration; it may resemble
subarachnoid haemorrhage. It is important to recognize this syndrome,
because computed tomography (CT) done as the initial diagnostic
procedure may not detect the adenoma owing to bony artefact at the
skull base or to incomplete evaluation by the person interpreting the
scan. Magnetic resonance imaging (MRI) should be performed if this
condition is suspected.
Loss of
libido is found most often in men. There may also be other symptoms and
signs of panhypopituitarism in either men or women, with amenorrhea,
sexual disinterest, smooth, pale skin, and chronic fatigue. These
clinical findings are supported by base-line hormone levels that
indicate significant pituitary insufficiency.
Some
nonsecretory pituitary adenomas today present as a sellar or suprasellar
mass found incidentally on a CT or MRI scan obtained to evaluate a head
injury or other unrelated problem. The management of a patient with this
finding requires considerable judgment and skill, as it is hard to make
the patient's symptoms better by any treatment. If there is a danger of
optic nerve compression or extension into the cavernous sinus, however,
or if there is a likelihood of pituitary gland compression,
transsphenoidal surgery is indicated unless there is a medical
contraindication.
Endocrine
Testing
Apparently nonfunctioning adenomas may be associated with abnormal
results on serum endocrine studies; these studies should be done as part
of the comprehensive workup of an apparently nonsecretory lesion.
Baseline endocrine testing includes assays of serum prolactin, growth
hormone, cortisol, triiodothyronine (T3), thyroxin (T4), FSH, and LH.
If the alpha subunit can be easily tested, it should also be measured.
There is currently discussion over the
need for preoperative stimulation studies. Although such studies may be
instructive, it is probably more important to obtain them
postoperatively, as the results may change after surgery. The use of
these tests depends in large part on the endocrinologists with whom the
pituitary surgeon collaborates.
Prolactin
may be elevated because of stalk compression in a non secretory adenoma.
This occurs because prolactin secretion is regulated mainly by the
inhibitory action of dopamine, which is released into the portal system
of the pituitary stalk. Compression of the stalk impedes the transfer of
dopamine, leading to an increased release of prolactin from pituitary
lactotropes. A large sellar and suprasellar tumour with a prolactin
level less than 200 ng/ml is more likely to be a nonfunctioning adenoma
than a prolactinsecreting one. A trial of bromocriptine may be helpful
in establishing that the tumour is non secretory, but if there is visual
compression, a better alternative is surgical decompression and
immunohistochemistry to establish the diagnosis.
Growth
hormone and cortisol levels will usually be normal in patients
on baseline testing but may show an abnormal lack of response to stress
testing. Failure of growth hormone to rise during an insulin tolerance
test or of ACTH and cortisol to rise during injection of corticotropin-releasing
factor are suggestive of hypofunction of the pituitary.
FSH, TSH,
and LH may be elevated in apparently non secretory pituitary
adenomas, as the clinical symptomatology of these hypersecretion
syndromes is mild. A measurable elevation of these hormones in serum
places the tumour in the category of glycoprotein secreting tumors,
rather than non secretory adenomas. Tumors with this hypersecretion have
the advantage of being associated with measurable serum changes, so they
can be followed easily. Hypersecretion of the alpha subunit associated
with glycoprotein hormones is also found in a substantial fraction of
patients with apparently "nonsecretory" adenomas. Using a sensitive
monoclonal assay, Oppenheim and colleagues reported that 37 percent of
patients with clinically nonfunctioning adenomas had elevated levels of
the alpha subunit in their serum.
Low
levels of FSH and LH may be an important early sign of hypopituitarism
associated with a nonsecretory adenoma. Looking at a series of 26
patients with large nonfunctioning adenomas, Arafah found GH deficiency
in 100 percent of patients, hypogonadism in 96 percent, hypothyroidism
in 81 percent, and adrenal insufficiency in 62 percent. Prolactin levels
were low in 5 patients, normal in 9, and elevated in 12. Unless there
are symptoms of diabetes insipidus, it is not worth doing water
deprivation tests or other tests of posterior pituitary function, even
with large nonsecretory adenomas.
Postoperative endocrine testing is an important component of the ongoing
evaluation of a patient. It should be postponed until acute surgical
effects have passed, usually at least 2 weeks after operation. It should
also include both baseline and stimulation studies.
Neuro-ophthalmologic
Testing
Formal visual field and acuity testing
are important in the evaluation of a patient with a nonfunctioning
adenoma, especially if imaging studies show the tumour reaching the
chiasm. The most usual finding is blurring of the temporal fields, but
homonymous hemianopia from tract compression, enlarged central scotoma,
and visual acuity loss are also possible. El Azouzi and colleagues
found that 68 percent of patients with visual symptoms and a pituitary
tumour had bitemporal field defects, but 5 percent had homonymous hemianopia because of retrosellar extension of
tumour and compression of
the retrochiasmatic optic system. It is important to recognize optic
atrophy preoperatively because it suggests that recovery of visual
acuity will not be complete in the affected eye.
Postoperative ophthalmologic follow-up should be carried out if there
was a preoperative visual deficit but may not need to be a regular part
of the long-term management if the patient has no visual symptoms and
imaging studies show resolution of chiasmal compression.
Imaging
Studies
By far
the most useful imaging study for a pituitary adenoma is MRI. Scanning should be done without and with gadolinium contrast
administration and in coronal sagittal, and transaxial planes. MRI can
demonstrate the configuration of the tumour, exclude an aneurysm.
establish the degree of retrosellar or parasellar extension. and
indicate the internal architecture of the tumour, including whether it is
cystic or contains haemorrhage.
On MRI
non secretory pituitary adenomas are usually associated with
an enlarged sella turcica. It is worth noting the pattern of extension
of the tumour; if there is substantial enlargement of the sella and the
tumour has a smooth suprasellar contour, there is likely to be an intact
diaphragma sellae that will allow vigorous curetting; if the sella is
modestly enlarged and the tumour appears to "spill
over" into the suprasellar region, care should be taken in curetting
above the sella. If there is major lateral extension to the cavernous
sinus, resection via a transsphenoidal or any other route will be
incomplete, and the surgeon should recognize this fact from the
beginning.
If a
patient is unable to have an MRI because of extreme claustrophobia or
the presence of a pacemaker or other ferromagnetic prosthesis, CT
without and with contrast enhancement may be used instead. CT scanning
should be done in coronal as well as transaxial planes. Skull tomograms
are not useful when CT or MRI can be done. Similarly, an angiogram is
not necessary if MRI is available. If MRI cannot be performed, however,
and the lesion has a regular ovoid or spherical shape in the suprasellar
region on CT, angiography may be indicated to exclude an intrasellar
aneurysm.
Differential Diagnosis of a Nonsecretory Pituitary Adenoma
There are
a number of sellar and suprasellar lesions that may resemble nonsecretory adenomas on imaging. These can be divided into two types:
masses of pituitary origin and masses of nonpituitary origin.
Among
pituitary lesions that may resemble a non secreting adenoma clinically
are prolactinomas and FSH- or LH-secreting adenomas. A prolactinoma may
present as a large mass with no hormone elevation except for prolactin.
With a large prolactinsecreting tumour. serum prolactin is usually
elevated into the thousands of nanograms per millilitre. If the
prolactin level is less than 200 ng/ml and the tumour is larger than 1 cm
in diameter. the tumour is most likely a nonsecretory adenoma. A trial of
bromocriptine treatment may also help in distinguishing a prolactinoma
from a nonsecreting tumour; if the tumour shrinks dramatically in response
to 5 to 10 mg of bromocriptine a day. it is most likely prolactinsecreting. About 20 percent of nonfunctioning adenomas show some response to bromocriptine,
however. It is important to be aware of this possibility and to use
regular imaging studies as well as endocrine testing in following tumors
of this description, as otherwise
one may be unaware that a presumed "prolactinoma" is continuing to grow
despite low prolactin levels.
Other
pituitary tumors that may resemble nonfunctioning tumors are those that
produce FSH and LH or alpha subunit. These tumors can be identified with
appropriate hormone testing and can be followed by both imaging and
hormonal testing. Rarely, a pituitary abscess will resemble a
non-secretory pituitary adenoma. There may be few symptoms associated
with this.
The
nonpituitary lesions that may resemble pituitary adenomas on imaging can
be divided into benign tumors, malignant tumors, cysts,
and miscellaneous lesions. Among the benign tumors are
meningiomas and craniopharyngiomas. Meningiomas usually arise from
the tuberculum sellae or the dura of the pituitary fossa. They are
homogeneous in consistency and enhance brightly: close MRI examination
may show an intact pituitary beneath them. They also tend to flatten at
the base and there may be associated hyperostosis of the tuberculum
sellae. Craniopharyngiomas are cystic or inhomogeneous
lesions that may occupy the entire sella or expand above it;
they may show calcification on CT. It is relatively unusual for a
pituitary adenoma to be cystic, although old haemorrhage may make it so.
It may be
difficult to distinguish craniopharyngiomas or cystic nonfunctioning
pituitary adenomas from other cystic lesions. Rathke's cleft cysts.
arachnoid cysts. and non-specific epithelial cysts may
occur in the pituitary or in its stalk. Rathke's cleft cysts are
homogeneous lesions of the stalk and are usually asymptomatic.
Arachnoid cysts have the same absorption characteristics as
cerebrospinal fluid. Epithelial cysts may be difficult to distinguish
from nonfunctioning adenomas except by surgical exploration.
A number
of malignant tumors may also occupy the sella, and it is important to
consider them if a conservative approach is taken to a pituitary mass.
Primary malignancies that may occur around the sella include chordomas
and chondrosarcomas (which are usually distinguished by the presence of
bony erosion and of calcification in a less dense matrix), malignant
gliomas of the posterior pituitary gland, and an unusual tumour called
granular cell myoblastoma, which appears to arise from embryonic tissue
in the sellar region. Metastatic tumors may occur in the pituitary fossa
and are radiologically indistinguishable from pituitary adenomas. The
most common sites of origin are breast and lung. The best differential
point in their diagnosis is their tendency to produce diabetes insipidus
and/or eye movement weakness early in their course.
Pathology and Pathophysiology
The
glycoprotein hormones are distinguished by their protein structure, with
a common alpha subunit and distinct beta subunits that give each hormone
its characteristic activity. An important initial step in the
understanding of nonsecretory adenomas was the observation that most of
them stain for the glycoprotein hormone subunits by immunohistochemical
techniques; this has been shown to be true of the messenger
ribonucleic acid (mRNA) for these subunits as well. However, the
subunits produced by these tumors do not seem to be able to combine to
provide receptor activation as normal pituitary hormones do, There are
also fragments of other hormones in clinically nonsecretory adenomas:
growth hormone production may occur; mRNA for prolactin and ACTH can
be found in a small number; and a compound called chromogranin A may
be an important assayable compound in these adenomas.
The study
of clinically non secretory adenomas in culture has been an intriguing
lesson in pituitary physiology. Kwekkeboom and colleagues demonstrated
that, although most of these tumors released gonadotropins or their
subunits in vitro, they usually did not do so in vivo, and responses to
TRH and bromocriptine did not depend on baseline hormone levels.
The
molecular biological origin of these tumors has not been easy to
elucidate. They appear to be monoclonal in origin. Activated forms of
G protein do not appear to be crucial in their initial development.
Platelet-derived growth factor, a growth factor important in a number of
human tumors, does not appear to be important for pituitary adenomas.
Treatment
Possible
treatments for non secretory pituitary adenomas include observation,
medical treatment, surgery by either the transsphenoidal or the
cranial route, and radiation therapy.
Observation Alone
Small,
silent pituitary adenomas may be treated by observation only; their
natural history cannot be predicted, but MRI permits close follow-up.
Asymptomatic pituitary masses less than 5 mm in diameter can be followed
initially with MRI scans.
Pharmacotherapy
Treatment
with a dopamine agonist such as bromocriptine has had variable success
for nonsecretory adenomas. Sassolas and colleagues reported some
shrinkage of tumour in 15 percent of patients receiving this treatment,
but nothing like the dramatic shrinkage seen with prolactinomas.
Based on
stimulation and inhibition studies of human tumors in culture, Klibanski
and colleagues have suggested that somastatin inhibits intact
glycoprotein or subunit secretion in most clinically nonfunctioning
pituitary tumorsl4; perhaps a somatostatin analogue will be a useful
agent if it can be made pharmacologically stable.
Transsphenoidal Surgery
The
treatment of choice for non secretory pituitary adenomas larger than 10
mm is surgical resection. Almost all pituitary adenomas can be treated
initially by transsphenoidal surgery. Exceptions are tumors that are
associated with a relatively small sella turcica or that have major
parasellar or presellar extension. In these cases, transcranial surgery
is a better approach.
The reason for frequent using of the transsphenoidal
approach is the fact that complete removal of most of these tumors is
impeded by cavernous sinus involvement. Tumors in the sinus cannot be
removed with satisfactory morbidity by either the transcranial or the
transsphenoidal approach, so the less morbid transsphenoidal resection
is to be preferred.
For the
transsphenoidal approach, an arterial line is
usually not used, a lumbar drain is not inserted, and the patient
receives hydrocortisone and antibiotics during anaesthesia induction. Approach
to these tumors transnasally, carrying out the entire procedure
using the operating microscope. The patient is positioned supine with
head elevated slightly and turned 30 degrees to the right. A C-arm
fluoroscope is used to visualize the sella. The operating microscope is
brought in from the beginning. The skin of the nose and right lower
abdominal quadrant are prepared with Betadine. The nasal mucosa is
infiltrated with 1:400,000 epinephrine/0.5% xylocaine and incised along
the left nasal septum starting just behind the mucocutaneous junction. A
mucosal flap is elevated with a caudal dissector. The septum is cracked
from left to right just in front of the sphenoid prow, but is not
removed. A nasal speculum is placed, and the sphenoid prow is removed by
chisel, taking care to produce a large enough fragment to close the
sella. The floor of the sella turcica is drilled with a high-speed air
drill or, if it is enlarged and thin, is opened with micro-pituitary
rongeurs. The sella is opened widely-to the cavernous sinuses
bilaterally and to the horizontal plane inferiorly. The dura is
coagulated by touching a metal suction tip with a Bovie
electrocoagulator on low power and is opened in an H shape or as a
window. If bleeding from venous dural sinuses is
encountered, it can usually be stopped by packing with Surgicel and applying compression for several minutes. Allowing
the sinus to close by opening the dura more widely may also facilitate
haemostasis. It is very important to achieve a dry field at this time.
Tumour
resection should begin with the posterior and inferior portion of the
tumour, gently using a variety of sizes and shapes of curette. A non
secretory tumour is usually not hard to identify because it is usually a
large mass. There may be a layer of normal anterior gland in front of
the tumour, but there is usually no choice but to open through this.
If the
opening in the sella is made too low, the posterior lobe may be mistaken
for tumour and resected. The posterior lobe is pale white and soft; large
tumors usually destroy it, but with tumors less than 1.5 cm in diameter
it may still be present.
If there
is considerable bleeding from the tumour, visible sources should be
coagulated with the bipolar cautery or gently packed with Surgicel and a
cottonoid patty; usually the bleeding will stop with time. Special
attention should be paid to the inferior aspects of the tumour at this
time; it is disappointing to spend a long time on the suprasellar
extension of a tumour and then see a large inferior residual on
postoperative MRI. The lateral pillars of the tumour should gently be
removed next; sometimes these are firm and unyielding, but every
attempt should be made to remove them to allow the suprasellar tissue to
collapse into the sella. Care should be taken to avoid injuring the
carotid arteries and cavernous sinus during this manoeuvre. A
preoperative review of the MRI scans is important to assess how
significantly tumour surrounds the arteries. If the tumour is very
fibrous, it may be difficult to dissect it from surrounding tissue. The
superior aspect of the tumour is left to last; if there is residual
pituitary, it is usually possible to dissect the tumour away from it
easily, and usually it is found packed against the back wall of the
sella.
Pathologic examination has varying usefulness in demarcating tumour from
normal gland. If the pathologist is experienced and can work quickly, a
frozen section may be very helpful, but in many cases the surgeon is
forced to rely on his or her surgical judgment.
The
management of the diaphragm a sellae is sometimes problematic.
If tumour is adherent to it, it should be removed even if there is a
resulting cerebrospinal fluid (CSF) leak. If CSF is seen at the time of
surgery, the sella is packed with fat harvested from the right lower
quadrant; a fragment of sphenoid prow is inserted into the sellar
opening; and fibrin glue made with autologous serum is used to seal the
sella. A Valsalva manoeuvre is used to test for further leaking.
A number
of techniques have been suggested for sealing an obvious and serious
leak. One is to use fascia lata and fat to obliterate the sella. Our
practice is to obliterate the sphenoid sinus with a combination of fat
and oxidized cellulose cotton. Packs of bacitracin-coated finger cots
or those with a nasal airway in them are placed in the nostrils, and the
patient is maintained on antibiotics for 72 h while the packs are in
place. Care must be taken to be sure that the mucosal flap is replaced
over the septum. The patient is allowed
to go home on the fourth postoperative day with maintenance steroids.
Postoperative MRI is done either within 48 h or after 1 month.
Results
of Surgery
The
success of surgery for non secretory adenomas can be measured with four
parameters: improvement in vision, improvement in
endocrine function, radiographic removal of tumour, and
paucity of complications. The literature gives data on the success of
transsphenoidal surgery by each of these criteria. Sassolas and
colleagues reported improvement in vision in 80 percent of patients and
radiographically complete removal of the tumour in 70 percent. In 20
percent there was evidence of continued growth even after radiation
therapy. Improvement in vision in 72 percent, diminished endocrine function
compared with the preoperative level in 3 percent, and complete
radiographic removal in 66 percent. Endocrine improvement may be
expected in about two-thirds of patients. The preoperative response to thyroid-releasing hormone (TRH) was an
important predictive test.
Complications of Surgery
Intraoperative Complications
Transsphenoidal surgery should only be
done by a surgeon familiar with the technique, since major morbidity may
result from the smallest deviation from a safe path. Among the potential
dangers are persistent CSF leakage, injury to the carotid artery,
damage to the midbrain or pons, haemorrhage in the sella turcica, loss of
anterior pituitary function, and diabetes insipidus. Each of these has
less than a 1 percent likelihood of occurring, but any of them can be
devastating.
The most
common complication is a CSF leak, which occurs in about 3 percent of
patients. Every effort should be made to avoid this
problem, as noted above. A lumbar drain should be inserted if there is
postoperative evidence of a leak, taking great care not to allow
pneumocephalus. The drain should be kept in place for up to 10 days;
if the leak has not stopped at that point, repeat surgery with packing
of the sphenoid sinus or other site of leakage should be carried out.
The
second most common complication is prolonged diabetes insipidus, which
presumably results from stalk injury; this should be avoided by careful
curet use.
Intrasellar haemorrhage occurs in 1 percent or fewer of pituitary
adenoma resections. It can be minimized by meticulous haemostasis, which
may involve use of the bipolar cautery, judicious use of Surgicel, and
patience in waiting for spontaneous haemostasis.
Loss of
pituitary function can be avoided by carefully identifying the normal
anterior pituitary during the curetting and avoiding removing it. Loss
of posterior lobe function can similarly be avoided by identifying this
lobe accurately and avoiding injury to it.
The most
serious potential complication is injury to the carotid artery, which
occurs in 1 percent or fewer patients. One should know from the MR scans
where the carotid artery is and avoid curetting or manipulating it. Any
haemorrhage should be immediately stopped by pressure and packing, and
postoperative angiography should be done to detect false aneurysm
formation.
Delayed
Complications There are several delayed complications that may follow
surgery for these tumors. Diabetes insipidus may occur after resection
of medium-sized tumors in patients who had good posterior lobe function
preoperatively. It is not a major problem because of the availability of
desmopressin acetate (DDAVP), but it should be recognized early. More
insidious is a phenomenon of inappropriate vasopressin secretion that
may follow surgery by 4 to 7 days. With this condition, a patient may appear in
the emergency room 8 days after a procedure with nausea and vomiting
and a sodium level of 125 mmol/litre or less. This sequela can best be
avoided by monitoring serum electrolytes closely for the first 2 weeks.
Sinusitis
may be a distressing problem, requiring antibiotics for 2 weeks or more.
Craniotomy
Craniotomy is used for pituitary adenomas
with supra-para-antesellar extension; when it
is used, a right pterional approach is one of the options; when there is
severe visual loss. the approach is through the side of the more
impaired eye, if the tumour configuration allow this, however, in
special situations approaching from the other side could be more
effective. The patient's head is turned 45 degrees to the left. and
the Mayfield head holder maintains position. An anterior curvilinear
incision is used; a small frontal flap is removed with care to get
anteriorly. The right frontal lobe is gently supported and, using an
operating microscope. the tumour is approached anterior to the chiasm.
posterior to it in the midline. or between the carotid artery and optic
chiasm. A variety of curettes are used to remove tumour tissue; the stalk
is preserved if possible.
Complications of craniotomy include seizures, impaired vision, frontal
lobe infarction or oedema. and unilateral anosmia.
Radiation
Therapy
Postoperative
radiation therapy in general use for nonfunctioning adenomas only if there is
residual tumour that is demonstrably growing. This differs from our
practice for functioning adenomas, in which irradiation is done if there
is an endocrine abnormality. This has been an area where radiosurgery is
particularly useful in our experience, and new techniques of radiosurgery or stereotactic radiotherapy will very likely become the
modality of choice for these lesions. A combination of surgery plus
radiation will provide 85 percent or higher tumour control over 20 years
