The transsphenoidal approach is the procedure of choice for the removal of pituitary tumors. The overwhelming majority of these tumors are benign adenomas and present either with characteristic syndromes of excess hormone secretion or secondary to mass effect on the normal pituitary or on the optic nerves. This mass effect on the pituitary can cause varying degrees of hypopituitarism and pressure of the optic pathways will produce visual field deficits. Effective medical therapy is available for prolactin secreting adenomas. With the exception of these tumors, transsphenoidal surgery remains the first-line treatment for most other pituitary adenomas.

Key words: pituitary adenoma, transsphenoidal surgery

CLASSIFICATION

Pituitary adenomas may be classified clinically according to size or functional status (Table 1). Those tumors that measure 10 mm or less in diameter are considered microadenomas; macroadenomas are those larger than 10 mm. Macroadenomas may also be sub-categorized as "giant" if their extent reaches far beyond the normal confines of the pituitary region. The functioning adenomas cause distinctive clinical syndromes that include acromegaly (growth hormone secreting adenomas), amenorrhea and galactorrhea (prolactin secreting adenomas), and Cushing's disease (corticotropin secreting adenomas). The non-functioning adenomas have no endocrine features other than hypopituitarism (decreased pituitary hormone production) and generally present either incidentally or secondary to mass effect.

EPIDEMIOLOGY

Pituitary adenomas account for approximately 10 to 15% of primary brain tumors (2,5,30,33,48). The incidence appears higher in African Americans in whom pituitary adenomas account for over 20% of tumors originating in the central nervous system (12,14). Although the incidence varies according to age, sex, and ethnic group, between 0.5 and 8.2 per 100,000 in the population are diagnosed annually with a pituitary adenoma (2,39,42). Autopsy series indicate that pituitary tumors are quite common and that nearly 25% of the population may harbor undiagnosed adenomas (6,46). The majority of these tumors are less than 3 to 5 mm and would not require medical or surgical intervention. More recent series using magnetic resonance imaging (MRI) of healthy subjects indicates that approximately 10% of the population harbors pituitary lesions. Some series report a higher rate of diagnosis among women of childbearing age. However, women may not actually have a higher incidence of pituitary adenoma (2,42). Because disruption of the pituitary axis affects reproductive capacity, women with pituitary adenomas may simply present at a higher rate than men.

Amongst the varying classes of adenomas, prolactinomas and non-functioning adenomas have the highest incidence, accounting for nearly two-thirds of all pituitary tumors. Prolactin secreting adenomas account for 40 to 60% of functioning adenomas and are the most common subtype of pituitary tumor diagnosed in adolescents (5). The majority of microadenomas are found in women in their second and third decades. Men generally present later, in their fourth and fifth decades, almost always with macroadenomas.

GH secreting adenomas represent nearly 30% of all functioning tumors. Nearly three quarters of GH secreting adenomas are macroadenomas. Approximately 40 to 60 individuals per million have acromegaly (1,10,41). Between 3 and 4 new cases per million are diagnosed annually (1,4,10,41). Most present in their 3rd to 5th decades after they have been developing symptoms and signs for many years (10). Acromegaly is associated with an increased incidence of cardiovascular, respiratory, cerebrovascular, and malignant disease. Accordingly, studies report an increased risk of mortality compared to the unaffected population (1,4). Although some studies report a higher incidence of several cancers, others have only confirmed an increase risk of colon cancer (16,36,40). There is some evidence that mortality risk may be different between the sexes. Etxabe found a higher mortality rate in men than in women (10). Other reports find similar degrees of increased mortality in both sexes (34). Still others report increased risks of death in men from cardiovascular, respiratory, cerebrovascular, and malignant disease, but only from cerebrovascular disease in women (1).

ACTH adenomas account for 15 to 25% of all functioning adenomas and are the most common pituitary tumors diagnosed in pre-pubertal children (5). The majority of ACTH adenomas, regardless of age, are microadenomas. Approximately 39 individuals per million have Cushing's disease and the annual incidence is estimated at 2.4 per million (11). Cushing's disease is more common in women, most of whom present in their third and fourth decades (11,15). There is a high incidence of hypertension and diabetes mellitus as well as higher vascular disease-related mortality (11,43).

CLINICAL PRESENTATION

Advances in computed tomography (CT) and magnetic resonance imaging (MRI) techniques have improved the visualization of the pituitary region. Increasing numbers of adenomas are being diagnosed incidentally during the evaluation of sinus disorders, trauma, and headache. These "incidentalomas" are not necessarily asymptomatic. Although visual deficits are discovered in fewer than 5%, some degree of pituitary dysfunction is found in up to 15% (13). More than one third are macroadenomas and, of these, approximately 25% will show significant enlargement over time (7,13,31,32). Asymptomatic incidental microadenomas are less likely to have clinically significant growth and often can be observed with repeated MRIs.

Most often, pituitary adenomas present secondary to hypersecretion, hypopituitarism, or mass effect (Table 2). The more prevalent hypersecretory syndromes include acromegaly associated with a GH secreting adenoma, Cushing's disease from an ACTH secreting tumor, and hypogonadism-galactorrhea resulting from a PRL producing adenoma. Hypopituitarism and mass effect occur most often in the setting of macroadenomas.

Hypersecretory Syndromes (for detailed descriptions see other

Acromegaly presents with characteristic cosmetic changes. There is an insidious coarsening of facial features with an enlarged forehead, enlarged tongue, malocclusion of the teeth, and prognathism. Patients' hands and feet also enlarge. Many patients also report excessive sweating. The external hypertrophy of tissue is paralleled within the body. Patients suffer enlarged organs and overgrowth of joints and cartilage, along with high blood pressure, congestive heart failure, sleep apnea, spinal canal narrowing, and carpal tunnel syndrome. Significant numbers of patients with acromegaly also have impaired glucose metabolism and, often, diabetes mellitus.

Cushing's disease causes changes in body habitus with increased weight, truncal obesity, "buffalo hump", and moon facies. Skin changes are also common and include purple striae, easy bruisability, ruddy complexion, and increased body and facial hair. Patients suffer from fatigue, proximal muscle weakness, osteoporosis, psychological disorders, high blood pressure, and impaired glucose metabolism.

Prolactinomas classically present with amenorrhea or oligomenorrhea and galactorrhea. These are generally women in their childbearing years who are more likely to pursue medical attention for infertility and menstrual irregularity. Men, and women beyond their reproductive years, more often have headache, visual symptoms, and signs of decreased pituitary function.

Amenorrhea and galactorrhea are not specific to prolactinomas, however. Prolactin secretion is under constant inhibitory control from the hypothalamus. Any lesion that imposes pressure upon the portal venous connection of the stalk connecting the brain and pituitary gland will interrupt these inhibitory signals, increase serum prolactin, and mimic a prolactinoma ie a 'pseudoprolactinoma'. In such cases serum prolactin levels are usually only moderately elevated. As a general rule, serum prolactin levels over 200 ng/ml (3600mu/l)are associated with prolactinomas.

Hypopituitarism

Tumor growth impairs the normal secretory function of the anterior pituitary and causes hypopituitarism. Common complaints include diminished sex drive, fatigue, weakness, and hypothyroidism. Pituitary insufficiency generally develops slowly over time. Acute pituitary insufficiency occurs in the setting of pituitary apoplexy, a condition in which the tumor infarcts or has internal bleeding. Apoplexy can be particularly devastating because it combines acute hypopituitarism with a rapidly expanding intracranial mass.

Neurological Dysfunction

Neurologic signs and symptoms develop as adenomas grow and exert pressure upon adjacent brain structures. Headache, although a non-specific complaint, can occur when a tumor stretches the dural sac that surrounds the pituitary gland. Visual deficits and diminished visual acuity arise as tumors grow and compress the optic nerves and optic chiasm. Classically this causes a bitemporal hemianopsia, visual loss in the temporal fields of each eye. Tumor growth may also affect other nerves(such as the first division of the trigemnial nerve, the 3rd, 4th or 6th cranial nerves) and cause facial pain and/or double vision or drooping of the eyelid.

DIAGNOSIS

Endocrinological tests can often confirm the clinical diagnosis of pituitary adenoma. Serum GH and IGF-1 levels screen for acromegaly. Failure to suppress GH levels after an oral glucose load (oral glucose tolerance test [OGTT]) confirms the diagnosis. Although any macroadenoma may cause moderate increases in serum PRL, levels greater than 200 ng/ml (3600 mU/l) are highly suggestive of a prolactin secreting adenoma.

Endocrinologic studies that suggest Cushing's disease include an elevated 24-hour urine free cortisol (UFC), loss of the normal daily variation in cortisol levels, and suppression of serum cortisol levels after high dose dexamethasone but failure to suppress after low dose dexamethasone. Petrosal vein sampling after corticotropin-releasing hormone (CRH) stimulation may be required to confirm and localize the pituitary source. Prior to diagnosing Cushing's disease, other ectopic sources of excess ACTH, such as bronchogenic or pancreatic carcinoma and pulmonary carcinoid tumors , must be excluded. This can usually be accomplished with a CT scan of the chest and abdomen. Obesity, alcoholism, and depression also elevate serum cortisol levels and the diagnosis of Cushing's disease should be made with caution in these settings.

TREATMENT

Although incidental microadenomas that do not cause symptoms may be followed clinically and with repeated MRIs, the remainder generally requires medical or surgical intervention. Therapeutic goals are improved quality of life and survival; elimination of mass effect and reversal of related signs and symptoms; normalization of hormonal hypersecretion; preservation or recovery of normal pituitary function; and prevention of recurrence of the pituitary tumor.

Medical Therapy

Medical therapy is available for some hypersecretory tumors (35,37,44,45). Most prolactin secreting adenomas are effectively treated with dopamine agonists (eg. bromocriptine, cabergoline). Surgical intervention is reserved for those who are intolerant of medical therapy, whose prolactin levels remain elevated or whose tumors continue to grow despite maximal medical treatment.

Medical treatment using somatostatin analogues or dopamine agonists has varying degrees of efficacy for treating GH adenomas. The recently described growth hormone receptor anatagonist, pegvisamont, may prove more effective (38). Currently, medical therapy is reserved for those patients awaiting surgery or those with persistent disease postoperatively. There is some evidence that pre-surgical medical therapy may improve surgical outcome (29).

Ketoconazole and/or metyrapone therapy can normalise serum cortisol levels in patients with Cushing's disease preoperatively. Like acromegaly, surgery remains the first-line therapy. The disadvantage of medical treatment of hypersecretory syndromes is that it is suppressive in nature. Tumors often recur when medications are discontinued.

Radiation Therapy

Radiotherapy is most often employed in conjunction with medical or surgical therapy. Fractionated external beam radiation therapy reduces excessive hormone production and can reduce the incidence of tumor recurrence (50). Gamma knife or linear accelerator stereotactic radiosurgery is increasingly applied to pituitary tumors and is also effective in normalizing hormonal hypersecretion and preventing recurrence (17,18,26,27). Whether by fractionated external beam or radiosurgery, the effects of radiotherapy are delayed. Patients require continued suppressive medical therapy during the period between treatment and effect. There is also a significant incidence of radiation-induced delayed panhypopituitarism (3,8,49,50).

Surgery

Indications for Surgery

1. For most pituitary tumors, surgery remains the first-line treatment of symptomatic pituitary adenomas. Surgery is also chosen secondarily when medical or radiotherapy fails; particularly for prolactin and growth hormone secreting adenomas. Surgery provides prompt relief from excess hormone secretion and mass effect. Surgery is also indicated in pituitary apoplexy with compressive symptoms regardless of the tumor type.

Surgical Approaches

1. The transsphenoidal approach can be used for 95% of pituitary tumors. Exceptions are those tumors with significant temporal or anterior cranial fossa extension. In such circumstances, transcranial approaches are often necessary. Occasionally, combined transsphenoidal and transcranial approaches are used.

2. The transsphenoidal approach is a versatile method for treating pituitary tumors (Table 4). Most often the entire surgery can be accomplished endonasally. Conversion to a sublabial approach is only necessary for large macroadenomas and children in whom the exposure through one nostril is often inadequate. Endoscopic approaches may be used in isolation or as an adjunct to the other transsphenoidal approaches (Fig. 1) (20-23). Computer-guided neuronavigational techniques are occasionally used in lieu of traditional fluoroscopic guidance (Fig. 2) (9,19). The role of neuronavigation is most pertinent in recurrent adenomas in which the midline anatomy has been distorted by previous transsphenoidal surgery. Extended transsphenoidal skull base approaches with a transsphenoidal transtuberculum sellae resection are useful for some large midline tumors with suprasellar or anterior cranial fossa extension (Fig. 3) (24,25,28,47).

3. Endonasal submucosal transseptal approach: The patient is placed in a lawn chair position and a hemi-transfixion incision is made just inside the nostril so that the scar cannot be seen after surgery (Fig. 4). A submucosal plane is developed to the level of the sphenoid sinus. Bone of the septum is harvested for use later in the operation. The bone surrounding the pituitary gland is also removed and tumor is extracted in small fragments. Afterwards the saved bone is used to refashion the normal housing of the pituitary gland. Closure is rapid and consists of several interrupted absorbable sutures in the nasal mucosa and temporary nasal packing to promote healing of the mucosa.

4. Septal Pushover/Direct Sphenoidotomy: Increasing numbers of surgeries are being performed using incisions deeper within the nasal cavity. The incision for the septal pushover technique is made at the junction of the cartilaginous and bony septum. Submucosal tunnels are developed on either side of the bony septum until the sphenoid sinus is reached. Another option to reach the sphenoid sinus is by performing a direct sphenoidotomy. Using this method, no incision is made in the septum. Instead the posterior part of septum just in front of the sphenoid sinus is deflected laterally and the sphenoid sinus is entered directly. There are several advantages to these techniques. Because there is no submucosal dissection of the cartilaginous septum, the risk of an anterior nasal septal perforation is eliminated. In addition, there is less of a need for nasal packing postoperatively, a frequent cause of postoperative pain and discomfort. The main drawback of these more direct approaches is that the exposure is not as wide as can be achieved by the standard endonasal transseptal approach in which the cartilaginous septum can be more extensively mobilized.

5. Pure endoscopic approach: The pure endoscopic approach is also increasingly being performed at selected centers. Surgery begins at the anterior sphenoid wall where the posterior septum is reflected laterally and an anterior sphenoidotomy is performed. After the sellar floor is opened, the endoscope is affixed to a specialized endoscope holder so that the surgeon can use both hands as is done in the microscopic adenomectomies. The endoscope provides a wider field of view than the microscope and because the local anatomy within the sphenoid sinus is so well visualized, intraoperative fluoroscopy most often does not need to be used. The option of using angled scopes allows surgeons to inspect for residual tumor particularly along the cavernous sinus walls and the suprasellar region. No nasal packing is required as the procedure is performed posterior to the septum. The main disadvantages are that the procedure has a learning curve and endoscopy does not provide a readily apparent depth of field to surgeons not familiar with endoscopy.

Figure 1. Endoscopic approach. This technique may be used either primarily for the approach to and removal of adenomas or as an adjunct to the microscopic adenomectomy.

Figure 2. Frameless stereotaxy. Preoperative images may be stored and used for image guidance during operative procedures. Above, an intraoperative photograph showing the surgeon (ERL) using intraoperative image-guidance. Note that the usual C-arm fluoroscope is not necessary. Below, captured computer screen image as viewed by the surgeon.

Figure 3. Extended skull base approaches. Pituitary tumors with extension along the anterior skull base may be approached transsphenoidally by removing the planum sphenoidale.

Figure 4. Standard endonasal approach. Left: above, patient positioning; below left, endonasal hemitransfixion incision; below right, alternative endonasal incision in sagittal view. Right: above, trajectory to sella in sagittal view; below, sequential steps used in tumor removal and repair of the sellar floor.

Outcome

1. Visual deficits in patients with non-functioning pituitary adenomas are improved in approximately 87%. Some visual deterioration may occur in 4%. Preoperative pituitary deficiency improves in 27% and the remainder of patients are managed with oral hormone replacement therapy. Operative mortality for these larger, and often, more invasive, tumors is slightly higher than for the functioning adenomas and reaches just over one percent. For similar reasons, tumor recurrence is also higher (Table 5). Ten-year recurrence rates are approximately 16%, although only 6% require additional treatment. On long-term follow-up, 83% of patients are alive and well without evidence of disease.

2. Using strict criteria for remission, transsphenoidal surgery obtains remission in 88% of patients with acromegaly with microadenomas and 65% of those harboring macroadenomas (Table 5). Acromegalic symptoms are improved in 95% and recurrence is less than 2 percent at ten years. Ninety seven percent of patients have preserved normal pituitary function. Seventy-two percent of patients with greater than ten year follow-up, including those with adjunctive therapy, are alive and well without evidence of active disease.

3. Patients with prolactinomas who present for surgery are most often those who have failed medical management. Prolactin levels are normalized in 87% of microadenomas and 56% of macroadenomas (Table 5). The recurrence rate among those patients who are normalized after a transsphenoidal operation is 13% at ten years. Preserved pituitary function occurs in all but 3%.

4. Surgical management of Cushing's disease achieves a 91% remission rate for microadenomas, but falls to 65% for those with macroadenomas (Table 5). While twelve percent of adults experience recurrence after ten years, a much higher percentage of children may develop recurrent Cushing's disease. Postoperative stereotactic radiosurgery has achieved remission in approximately 68% of patients whose disease either did not remit following surgery or recurred.

Complications of Transsphenoidal Surgery

1. 1. The overall mortality rate for transsphenoidal surgery is less than 0.5% (Table 6). Major morbidity (cerebrospinal fluid leak, meningitis, stroke, intracranial hemorrhage, and visual loss) occurs in between 1 and 2% of cases. Less serious complications (sinus disease, nasal septal perforations, and wound issues) occur in approximately 6.5%.

CONCLUSION

Pituitary adenomas are a complex set of benign tumors that present with characteristic hypersecretory syndromes and mass effect. Although medical and radiotherapy offer effective treatment for particular tumors in specific situations, transsphenoidal surgery continues to provide optimal outcomes for non-prolactin secreting adenomas with a low incidence of major morbidity.