Surgery for pituitary adenomas

By: Kalmon D. Post, Harel Deutsch, Wesley A. King

Keywords: pituitary adenoma; transsphenoidal surgery

Historical note and nomenclature

In 1908, Schloffer and Hochenegg performed the first successful transsphenoidal
surgery in Vienna (Hardy 1996). Harvey Cushing perfected the transsphenoidal
approach for sellar lesions in 1910. Cushing performed over 200 procedures before
adopting a transcranial surgical approach for pituitary lesions. The incorporation of the
operative microscope by Hardy and intraoperative fluoroscopy by Giout resulted in the
transsphenoidal procedure's resurgence. Today, transsphenoidal surgery for pituitary
adenomas is the most commonly employed surgery; craniotomies may, though, be
required for giant pituitary tumors.

Scientific basis
Knowledge of the pituitary's anatomy and physiology is essential to
understanding the surgical treatment of pituitary adenomas. A pituitary adenoma's
abnormal growth compromises the integrity of adjacent structures. Surgery places these
structures at risk and surgical complications are better understood in the context of the
pituitary's anatomy. The pituitary is contained within the sella turcica, a midline
depression in the sphenoid bone. The inferior border of the sella is the superior wall of
the sphenoid sinus. Above the diaphragma sellae is the suprasellar cistern containing the
optic chiasm and internal carotid arteries (Rhoton et al 1979). The cavernous sinuses are
located laterally to the sella and contain cranial nerves III, IV, V, VI as well as the
carotid arteries (Parent 1996).
Pituitary macroadenomas typically extend upwards, where they place pressure
on the optic chiasm. The classic visual field deficit encountered is a bitemporal
hemianopsia. Lateral tumor extension results in the involvement of the cavernous sinus.
Pituitary adenomas can encase the carotid artery but very rarely exert pressure on the
artery. Compromise of the cranial nerves in the cavernous sinus is also rare.
Involvement of the cavernous sinus makes complete surgical resection impossible
without significant morbidity.
The normal pituitary gland is composed of an adenohypophysis and a
neurohypophysis. The adenohypophysis originates as a diverticulum from the primitive
foregut and contains the effector cells of the neuroendocrine system. The
adenohypophysis is responsible for secreting 8 hormones: (1) growth hormone, (2)
prolactin, follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating
hormone, adrenocorticotropic hormone, melanocyte-stimulating hormone, and beta-
endorphin. Adenomas arising from endocrinologically active cells lead to hormone
overproduction and associated syndromes. Large tumors place pressure on normal
adenohypophysis cells and result in decreased hormone production. The
neurohypophysis arises as a diverticulum from the brain and is involved in regulation of
anterior pituitary function, the secretion of antidiuretic hormone, and oxytocin. Large
tumors can cause reduction of antidiuretic hormone secretion and result in diabetes
insipidus.
Pituitary adenomas account for 15% of all primary intracranial tumors. The vast
majority of these adenomas are benign. Surgical therapy is conducted in order to
decompress the mass effect of pituitary adenomas on neighboring structures and to
eliminate the overproduction of pituitary hormones such as growth hormone,
adrenocorticotrophic hormone, thyroid-stimulating hormone, and prolactin.

Indications
The widespread availability of MRI has resulted in the increased discovery of
incidental pituitary adenomas (Molitch and Russell 1990). Patients with pituitary
adenomas should be screened for hypopituitarism and for the oversecretion of pituitary
hormones. Formal visual field testing is done to exclude compression of the optic
chiasm. Patients with normal visual fields and normal hormone levels may be followed
with yearly serial MRIs. Only approximately 5% of patients with microadenomas
demonstrate significant tumor growth, whereas more than 25% of patients with
macroadenomas are found to have tumor growth. Surgery is indicated in patients with
visual disturbances, hormone deficiencies, increasing tumor size, and uncertain
diagnosis (Molitch 1997).
Transsphenoidal surgery is indicated for all patients with adrenocorticotrophic
hormone, thyroid-stimulating hormone, and growth hormone secreting adenomas. A
significant reduction of morbidity can be achieved with surgical cure of
adrenocorticotrophic hormone, thyroid-stimulating hormone, and growth hormone
oversecretion. Dopamine agonists are the preferred treatment for both
microprolactinomas and macroprolactinomas. Tumor shrinkage and normalization of
hormone levels are achieved in most patients. Surgery is indicated for patients with
prolactinomas not responsive to dopamine agonist therapy. Surgery is also indicated in
patients who cannot tolerate dopamine agonist therapy (Shimon and Melmed 1998).

Contraindications
Transsphenoidal surgery is a relatively safe procedure and is tolerated well by
patients; it has few contraindications. Appropriate patient selection is essential in
obtaining a good outcome. Patients with sphenoid sinus infections should not undergo
transsphenoidal surgery because of the risk of intracranial spread of infection and
meningitis. Tumor morphology may also dictate the operative approach. Tumors located
eccentrically may not be accessible transsphenoidally and require a transcranial
approach. If the tumor has a "dumbbell" shape, a constrictive diaphragma sellae may
limit adequate tumor decompression. Additionally, the tumor's consistency influences
the surgical outcome. Most adenomas have a soft consistency and are easily and safely
removed using curettes and suction. Firm tumors can be difficult to remove via the
transsphenoidal approach. Adequate preoperative radiological evaluation is essential
because of the wide range of pathologies found in the sella. For example, the
misdiagnosis of an aneurysm as an adenoma can result in a potentially fatal
complication. Any vascular anomalies in the sella region may represent a
contraindication for the transsphenoidal approach.

Goals and endpoint

The goal of surgery for pituitary adenomas is dependent on the patient's clinical
syndrome. The goal in surgery for macroadenomas is improvement in vision,
improvement in endocrine function, and radiographic removal of the tumor. If possible,
complete tumor resection is achieved, but often only a subtotal resection is possible.
Patients with residual tumors can be followed with serial MRIs, and either reoperation
or radiation therapy can be performed for tumor regrowth.
Normalization of hormone levels while preserving normal pituitary function is
the goal of therapy in endocrinologically active tumors. In prolactinomas, the goal of
therapy is the normalization of prolactin levels to less than 25 ng/ml for a period of at
least 5 years. Galactorrhea should cease and normal menstrual periods should resume
(Massoud et al 1996). The purpose of surgery in Cushing disease is the elimination of
adrenocorticotrophic hormone inappropriate secretion and to preserve normal pituitary
function (Styne et al 1984). Satisfactory results in growth hormone secreting tumors
include clinical improvements in the symptoms and signs of acromegaly and a fall in
serum growth hormone values to less than 2 ng/ml during a glucose tolerance test
(Freda et al 1998).

Description
Antiseptic povidone-iodine is applied to the nose and mouth, and the area is
draped sterilely. The left lower quadrant of the abdomen is prepared and draped to
obtain adipose tissue to seal the sella turcica and sphenoid sinus. A speculum is placed
into the right nare, and a lidocaine and epinephrine mixture is injected to develop a
dissection plane between the septum and the mucosa as well as facilitating hemostasis
through the epinephrine's vasoconstrictive effect. An incision is made in the nasal
mucosa near the border of the cartilaginous septum and the vomer with a scalpel. The
incision is carried down to the septum, which is then separated from the mucosa.
Alternatively, a midline sublabial incision allows for the submucosal dissection.
After the mucoperichondrial plane between the septum and nasal mucosa is
identified, it is developed posteriorly. The nasal septum is fractured at its base with a
small osteotome, allowing it to be displaced to the opposite side. Continued separation
of mucosa from the nasal septum in a posterior direction is carried out on both sides of
the vomer. The speculum is advanced between the septum and mucosa and opened
allowing one blade of the speculum to move across the midline and expose the anterior
wall of the sphenoid sinus. Maintaining a midline orientation is important in avoiding
complications.
The anterior wall of the sphenoid sinus is usually thin and is easily opened with
a rongeur. The sphenoid mucosa is cauterized and removed. A lateral skull fluoroscopy
is used to confirm proper location and trajectory to the sella. An opening is made in the
anterior wall of the sella with a small osteotome and then enlarged with a rongeur
(Hardy 1996).|{diagram:spahd5.bmp}{caption:Transsphenoidal surgery trajectory}
{label:During transsphenoidal surgery, a speculum is advanced through the nasal cavity
and sphenoid. Removing the posterior wall of the sphenoid reveals the dura and
pituitary gland.}|
An incision is made in the dura with a scalpel. The dural edges can be
coagulated with the bipolar cautery for hemostasis. Usually, the tumor is readily visible
and larger tumors often extrudes from the sella. The tumor is usually soft and can be
removed easily with blunt ring curets and suction. Larger tumors frequently erode the
floor of the sella and may be encountered in the sphenoid sinus. A thin, flattened
pituitary gland can usually be identified displaced posteriorly and superiorly.
Suprasellar tumor extension can be removed after evacuation of the intrasellar portion.
Raising the intracranial pressure with the infusion of Ringer's solution through a lumbar
subarachnoid catheter or by initiating a Valsalva maneuver can help facilitate the
descent of suprasellar tumor parts. The billowing arachnoid is visible after complete
tumor resection. Preservation of the arachnoid membrane prevents a postoperative CSF
leak but perforation is sometimes inevitable because of tumor involvement with the
arachnoid membrane.
The tumor bed usually stops bleeding after all neoplasm has been removed. The
tumor bed and sphenoid sinus are packed with adipose tissue taken from the abdomen.
Nasal Packing is placed in both nares to facilitate hemostasis.

Outcome
Transsphenoidal surgery is generally well-tolerated by patients, with few
significant complications. Patients typically only remain in the hospital for 2 to 5 days
postoperatively (Wilson 1992).
Remission rates for pituitary adenomas vary. Growth hormone secreting tumors
are effectively controlled in 80% of cases. Approximately 10% of patients with normal
postoperative growth hormone levels develop a recurrence of elevated levels and
require reoperation. Control rates are higher in patients with microadenomas (90%) and
lower in macroadenomas (50%) (Laws 1996; Freda et al 1998). An additional third of
patients achieve remission with radiotherapy after surgery. Some patients also achieve
clinical remission with the addition of medical therapy to surgery and radiotherapy.
Prolactin levels are normalized in 75% of patients after surgery. After resection
of prolactinomas, data indicate conception can be achieved in 90% of women within
one year after surgery. adrenocorticotrophic hormone secreting tumors are cured in 90%
of patients (Giovanelli et al 1996; Abosch et al 1998). Transsphenoidal microsurgery for
Cushing disease is the single best therapy when compared with drug or radiation
treatment. Thyroid-stimulating hormone secreting adenomas are very rare and surgical
treatment offers excellent treatment results.
Approximately 50% to 70% of patients operated on for pituitary macroadenomas
experience an improvement in vision postoperatively. Complete radiographic tumor
resection is achieved in 50% to 60% of patients with macroadenomas (Colao et al
1998). Residual tumor can be followed with serial MRIs, and recurrent tumor growth
can be treated either by reoperation or radiation therapy.

Adverse effects
Transsphenoidal surgery can be performed with extremely low mortality and
low morbidity. Mortalities have been reported as occurring in 0% to 1.75% of cases.
Morbidities associated with the transsphenoidal approach are distinct from general
neurosurgical complications because the approach is quite different from most
transcranial approaches (Ciric et al 1997).
Anesthetic complications in transsphenoidal surgery are rare. Specific mention
should be made concerning acromegalic patients. These patients exhibit
cardiomyopathy and macroglossia associated with a difficult intubation. Patients with
pituitary lesions are often deficient in 1 or more pituitary hormones. A comprehensive
preoperative endocrine analysis is essential and adequate stress doses of steroids should
be given. Postoperatively, the patients' endocrine status should be followed carefully.
Other medical complications are relatively rare and are commensurate with
complications in other elective procedures.
There are several complications that can arise as a consequence of the
transsphenoidal approach. If a sublabial incision is used, anesthesia of the upper lip and
anterior maxillary teeth can occur, although this condition is usually only transient.
Removal of the superior cartilaginous septum can potentially result in a saddle nose
deformity. Nasal septum perforation occurs in 1% to 3% of cases and is more likely in
reoperations. Postoperative sinusitis can occur in 1% to 4% of patients and can
potentially be reduced by postoperative antibiotics (Ciric et al 1997).
Vascular injuries represent serious morbidities and can lead to death.
Intraoperative mucosal bleeding and delayed postoperative bleeding can occur from the
mucosal branch of the sphenopalatine artery. Damage to the carotid arteries, although
rare, can occur in the sphenoid sinus or in the sella. Maintaining a midline trajectory
during surgery is essential to avoiding carotid injury. Preoperative radiological studies
are essential in localizing the carotid artery. There are significant variations in the
carotid's sellar course, and the distance between the 2 arteries can be only 4 mm or less.
Heavy arterial bleeding signals intraoperative injury to the carotid artery, and the only
treatment involves packing the operative field. Carotid artery injury can result in
subarachnoid hemorrhage, vasospasm, false aneurysms, and carotid cavernous fistulas.
A postoperative cerebral angiogram is essential to identify any of these complications.
Approximately 25% of deaths occurring during transsphenoidal surgeries are
attributable to vascular injuries.
Visual disturbances are also possible because of the close association of the
chiasm, optic nerve, and the pituitary. Damage can occur through direct trauma, traction
injury, or vascular compromise. In general, visual disturbances occur in 0.6% to 1.6%
of patients. Tumor bed hematomas develop in 0.3% to 1.2% of cases and can lead to
postoperative visual loss. Injuries to the hypothalamus can also occur and potentially
result in death. These patients are comatose and exhibit hyperthermia. Hypothalamic
injury represents the most common cause of death in transsphenoidal surgeries.
In the postoperative period there are several complications that can be
anticipated. Early recognition and appropriate treatment can circumvent catastrophic
results. Patients should be closely monitored for diabetes insipidus with frequent serum
sodium evaluations and careful accounting of patients' fluid intake and urine output. An
elevated serum sodium or excessive urine output may indicate diabetes insipidus. The
disease results from manipulation of the pituitary stalk. Temporary postoperative
diabetes insipidus occurs in between 10% to 20% of cases. Permanent diabetes insipidus
is much less common and only occurs in 0.5% to 5% of patients. Delayed onset of
syndrome if inappropriate antidiuretic hormone can also occur about a week
postoperatively, but is unusual.
Postoperative anterior pituitary insufficiency is one of the most commonly seen
postoperative complications. The incidence varies from 1% to 10%. Postoperative
steroid therapy should be utilized in all postoperative patients until a thorough endocrine
evaluation is complete. Adrenal insufficiency is a potentially serious complication if
adequate steroid replacement therapy is not initiated.
Cerebrospinal fluid rhinorrhea is another commonly encountered complication
of the transsphenoidal approach, occurring in 1% to 4% of cases. Intraoperatively,
penetration of the arachnoid membrane can result in a gush of CSF in the operative field
as well as the potential for postoperative CSF rhinorrhea. Patients developing CSF
rhinorrhea are first treated using spinal drainage for several days. Failure to close the
CSF fistulae using spinal drainage may indicate the need for reoperation with repair of
the sella. Early recognition and treatment of CSF rhinorrhea is important because a CSF
leak can lead to meningitis. The incidence of meningitis in transsphenoidal surgery is
0% to 1.75%.

Table 1. Common complication rates in transsphenoidal surgery

Complication Rate (%)
Death 0 to 1.75
Morbidity
Nasal septum perforation 1 to 3
Sinusitis 1 to 4
Epistaxis 2 to 4
Visual disturbances 0.6 to 1.6
Transient diabetes 10 to 20
insipidus
Permanent diabetes 0.5 to 5
insipidus
Anterior pituitary 1 to 10
insufficiency
CSF leak 1 to 4
Meningitis 0 to 1.75

Prognosis
Prognosis depends on the pituitary adenoma type. Since pituitary adenomas are
generally benign tumors, the prognosis is generally excellent. Transsphenoidal surgery
is well-tolerated with few complications. Ninety-nine percent of patients return to their
preoperative lifestyle or work within 2 weeks after surgery. . the long-term prognosis
for patients with acromegaly and Cushing disease depends on hormonal regulation.
Visual problems generally improve after surgery. Hormonal function may also improve
postoperatively (Feigenbaum et al 1996).
The surgical resection of growth hormone secreting pituitary adenomas results in
normal postoperative growth hormone levels in 80% to 90% of patients. Untreated
acromegalics have a 4-fold increased general mortality rate, whereas treated
acromegalics with growth hormone levels less than 5 ng/mL have normal life spans
(Abosch et al 1998).
Long-term follow-up on patients with prolactinomas indicates that up to 50%
have recurrences of hyperprolactinemia. Many of these patients have asymptomatic
hyperprolactinemia, and their postoperative prolactin levels are much lower than
preoperative level (Feigenbaum et al 1996). The best indicators of successful surgical
resection are a postoperative prolactin hormone level of less than 5 ng/mL and
histological diagnosis of prolactinoma on removed tissue (Massoud et al 1996).
Patients with nonfunctional pituitary macroadenomas who undergo surgery and
have residual tumor have a 25% tumor regrowth rate. Treatment for residual tumor may
involve either reoperation or radiation. Conventionally radiated tumors have a 15%
tumor growth rate (Colao et al 1998).

Clinical vignette
DR is a 52-year-old male who presented with a chief complaint of headaches
and blurry vision. His history was significant for approximately 9 months of diminished
libido and worsening impotence. He also complained of generalized fatigue and
decreased appetite. Physical exam was notable for a blood pressure of 110/60 and
bilateral gynecomastia. The patient demonstrated no Cushingoid or acromegalic
features.
Laboratory testing demonstrated testosterone 123 ng/dl (300 ng/dl to 1100
ng/dl), T4 3 mcg/dl (4-12 mcg/dl), thyroid-stimulating hormone 12 mU/ml (0.5 mU/ml
to 5.0 mU/ml), and prolactin 58 (less than 10 ng/ml). The somatomedin C level was
normal. Visual field analysis demonstrated bitemporal hemianopsia. A brain MRI
demonstrated a large sellar mass with suprasellar extension and compression of the
optic chiasm. The diagnosis of a clinically nonfunctioning pituitary adenoma was
made.
The patient was scheduled for elective transsphenoidal decompression. The
patient tolerated the surgery and was discharged home on postoperative day 3. DR noted
a near immediate improvement in his vision. An MRI performed 3 months
postoperatively demonstrated complete tumor resection.

Pregnancy
Hyperprolactinemia is a common cause of infertility; appropriate treatment with
bromocriptine or surgery will facilitate fertility. Pregnancy is not a contraindication for
transsphenoidal surgery. Patients with macroadenomas should have surgery prior to
pregnancy because the physiological increase in pituitary size during pregnancy can
result in optic chiasm compression.

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Acromegalic facial features

This patient demonstrates the classical coarse facies associated with acromegaly.
Surgery can lead to the reversal of acromegalic features.
MRI of giant pituitary macroadenoma
T1-weighted MRI reveals a giant macroadenoma not accessible by the transsphenoidal
approach because of the extensive suprasellar tumor extension.

MRI of pituitary macroadenoma (pre-operation)

Preoperative gadolinium enhanced T1 weighted image showing a large sella mass with
extrasellar extension.

MRI of pituitary microadenoma (1)

T1-weighted coronal MRI demonstrating a pituitary microadenoma. The pituitary
normally enhances, and adenomas appear as hypointense lesions within the pituitary
gland
MRI of pituitary microadenoma (2)
T1-weighted sagittal MRI showing a pituitary microadenoma. Note the position of the
sella and the pituitary gland within the sphenoid sinus

Pituitary macroadenoma (post-operation)

Postoperative gadolinium enhanced T1 weighted image performed 3 months after
surgery shows complete pituitary adenoma resection.

Sublabial transsphenoidal approach in pituitary adenoma surgery

An incision is made sublabially in the midline above the incisors.
Transsphenoidal surgery trajectory
During transsphenoidal surgery, a speculum is advanced through the nasal cavity and
sphenoid. Removing the posterior wall of the sphenoid reveals the dura and pituitary
gland.