Chapter 13 - Surgical Treatment of Pituitary Adenomas

Updated 1 December 2009

CLASSIFICATION

Pituitary adenomas may be classified either according to their size or their functional status (Table 1). Those tumors that measure 10 mm or less in diameter are considered microadenomas; macroadenomas are those larger than 10 mm (Fig. 1 a, b, c, and d). Macroadenomas may also be sub-categorized as "giant" if their extent reaches far beyond the normal confines of the pituitary region or their greatest diameter exceeds 4 centimeters (Fig 1e, f, and g). Pituitary adenomas may also be categorized as either hypersecretory or non-functioning. The hypersecretory adenomas cause distinctive clinical syndromes that include acromegaly/gigantism (growth hormone (GH) secreting adenomas), Forbes-Albright syndrome (prolactin (PRL) secreting adenomas), and Cushing's disease (corticotropin (ACTH) secreting adenomas). The non-functioning adenomas (NFAs) have no endocrine features other than hypopituitarism (decreased pituitary hormone production) and generally present either incidentally or secondary to mass effect.

Table 1. Classification Schemes of Pituitary Adenomas
Scheme	Features
Microadenoma/ Macroadenoma	 10 millimeters/ > 10 millimeters
Non-Functioning adenoma Functioning adenoma	Endocrinologically inactive, patient may present with pituitary deficiency. Excess of pituitary hormone secreting: GH adenoma; PRL adenoma; ACTH adenoma; TSH adenoma; GH and PRL adenoma; Other plurihormonal hypersecretory adenomas

 

Figure 1. Tumor Classification based on size. Microadenoma: Coronal and sagittal T1 weighted MRIs with contrast with arrow indicating the location of the tumor (a and b). Macroadenoma: Coronal and sagittal T1 weighted MRIs of a typical macroadenoma (c and d). Giant invasive macroadenoma: Coronal and sagittal T1 MRIs with contrast in a patient in whom the tumor compresses the right temporal lobe and invades the sphenoid sinus (e and f). In another patient, the sagittal MRI reveals a tumor that has not only invaded the sphenoid sinus but compresses the brainstem; the tumor is highlighted (g and h).

EPIDEMIOLOGY

Pituitary adenomas account for approximately 10 to 15% of primary brain tumors operated upon in the Unites States (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 in diameter and would not require medical or surgical intervention. More recent series using magnetic resonance imaging (MRI) of healthy subjects indicate 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 come to clinical attention at a higher rate than men.

Amongst the varying classes of adenomas, prolactinomas and non-functioning adenomas have the highest incidence, and account 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 increased 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 diagnosed incidentally during the evaluation of sinus disorders, trauma, cervical spine disease 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 followed over time with repeated MRIs.

Although an increasing number of tumors are diagnosed incidentally, pituitary adenomas more often present secondary to hypersecretion, hypopituitarism, or mass effect (Table 2).

Table 2. Presentation

Hypersecretion GH secreting adenoma: Acromegaly ACTH secreting adenoma: Cushing's disease Prolactin secreting adenoma: Amenorrhea-galactorrhea TSH secreting adenoma: Secondary hyperthyroidism

Pituitary insufficiency Symptoms: diminished libido, fatigue, weakness Gonadal dysfunction, Hypothyroidism, Adrenal Insufficiency, Somatotroph Insufficiency

Mass Effect (symptoms by compressed structures) Optic chiasm: bitemporal visual field deficit and possibly diminished acuity Cavernous sinus: trigeminal nerve, facial pain; cranial nerves III, IV, VI, diplopia, ptosis, mydriasis Pressure on dura or diaphragma sellae: headache Hypothalamus: behavior, eating, and vigilance disturbances (somnolence) Temporal lobe: complex partial seizures

Incidental Discovered during the evaluation for headaches, trauma, nasal sinus disorders

Hypersecretory Syndromes

(for detailed descriptions see other chapters in Endotext)

Acromegaly presents with characteristic structural changes. There is an insidious coarsening of facial features with an enlarged forehead, enlarged tongue, malocclusion of the teeth, and prognathism (Fig 2). 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 diabetes mellitus.

Figure 2. Acromegaly. A. Coronal T1 weighted MRI with contrast in a patient with a sellar GH secreting adenoma. Arrows indicate the common finding of “cutis gyrata”. B. Sagittal T1 weighted MRI in the same patient with arrows indicating the frontal bossing and * within the enlarged frontal sinus.

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.

Patients with prolactinomas classically present with amenorrhea or oligomenorrhea and galactorrhea. Most are women in their childbearing years and 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 dopaminergic signals. This, in turn, causes an increase in serum prolactin levels, and mimics a prolactinoma, i.e. 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. However, acute pituitary insufficiency may occur in the setting of pituitary apoplexy, a condition in which the tumor infarcts or has internal bleeding (Fig 3). 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 beyond the confines of the sella turcica and exert pressure upon adjacent brain structures. As tumors enlarge, they compress the optic nerves and optic chiasm and patients experience visual deficits and diminished visual acuity. 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 3rd, 4th, 5th, or 6th cranial nerves) and cause facial pain and/or double vision or drooping of the eyelid. Headache, although a non-specific complaint, can occur when a tumor stretches the dural sac that surrounds the pituitary gland.

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 late night salivary or 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. At times, 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 often be accomplished with a CT scan or MRI 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, patients with macroadenomas generally need 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 growth hormone receptor anatagonist, pegvisamont, may prove more effective and can be used in combination with other agents (38, 38a 38b)). Although medical therapy is most often reserved for those patients awaiting surgery or those with persistent disease postoperatively, some advocate primary medical therapy particularly for invasive tumors (38c, 38d). There is some evidence that pre-surgical medical therapy may improve surgical outcome (29).

Ketoconazole and/or metyrapone therapy can normalize 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 hypopituitarism (3,8,49,50).

Surgery

Indications for Surgery

For most pituitary tumors, surgery remains the first-line treatment of symptomatic pituitary adenomas. Surgery is also chosen secondarily when medical treatment or radiotherapy fails; particularly for prolactin and growth hormone secreting adenomas. Surgery provides prompt relief from excess hormone secretion and mass effect. There is evidence to suggest that debulking of medically refractory prolactinomas and GH adenomas can return these tumors to a responsive state (51, 52) Surgery is also indicated in pituitary apoplexy with compressive symptoms regardless of the tumor type.

The minimally invasive 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. Nevertheless, some surgeons extend the basic transsphenoidal exposure in order to remove some of these tumors and avoid a craniotomy (Fig. 3) (24,25,28,47).

The transsphenoidal approach is a versatile method for treating pituitary tumors (Table 4). Endoscopic approaches may be used in isolation or as an adjunct to the other transsphenoidal approaches (Fig. 4) (20-23, 53, 54, 55, 56, 57 ). Computer-guided neuronavigational techniques are occasionally used in lieu of traditional fluoroscopic guidance (Fig. 5) (9,19). The role of neuronavigation is most pertinent in recurrent adenomas in which the midline anatomy has been distorted by previous transsphenoidal surgery. Intraoperative MRI is increasingly available and appears most applicable for large tumors (58). There are three basic variations of the transsphenoidal approach.

Table 4. Transsphenoidal Surgery for Adenomas: Personal Case Summary (1972-2000)
Type of Adenoma Functioning adenomas	Number of Patients (%) N=3093
GH adenoma (Acromegaly)	537 (17.4)
PRL adenoma	889 (28.7)
ACTH adenoma (Cushing's disease)	490 (15.8)
Post-adrenalectomy ACTH adenoma (Nelson-Salassa syndrome)	65 (2.1)
TSH adenoma	39 (1.3)
Non-functioning adenomas	1073 (34.7)

1. 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. 6, lower left). Most often the entire procedure can be accomplished endonasally. Conversion to a sublabial approach may be necessary for large macroadenomas and children in whom the exposure through one nostril is often inadequate. A submucosal plane is developed along the nasal septum back to the level of the sphenoid sinus. Bone of the septum is harvested for use later in the operation. The bone in front of 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.

2. Septal Pushover/Direct Sphenoidotomy: Increasing numbers of pituitary operations are being performed using incisions deeper within the nasal cavity (Fig 6, lower right. 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 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.

3. Pure endoscopic approach: The pure endoscopic approach is also increasingly being performed at selected centers. Surgery begins at the anterior sphenoid wall where a direct anterior sphenoidotomy is performed. Some surgeons prefer to perform the surgery a using a single nostril. A binostril approach, however, provides more maneuverability. To achieve an adequate exposure for the binostril approach, the septum just in front of the sphenoid sinus is removed. This allows instruments to be used in both nostrils simultaneously. Although a specialized endoscope holder may be used during tumor removal, the “3-hand” technique is advocated by many surgeons. The “3-hand” technique requires two surgeons; one surgeon maneuvers the endoscope while another has both hands free to remove the tumor using microsurgical techniques. The endoscope provides panoramic magnified views of the sellar anatomy during both the approach to and resection of tumors (Fig 7a, b). The option of using angled endoscopes allows surgeons to inspect for residual tumor, particularly along the cavernous sinus walls and the suprasellar region (Fig 7c, d). No nasal packing is required as the procedure is performed posterior to the septum. The main disadvantages are the procedure’s learning curve and that the depth of field is less easily discernible to the unfamiliar surgeon.

Figure 3. Pituitary apoplexy. Sagittal T1 weighted MRI without contrast in a patient presenting with pituitary apoplexy. Note the fluid fluid level within the tumor indicative of the apoplectic tumor.

Figure 4. Endoscopic approach. Intraoperative photograph of one surgeon (left) driving the endoscope while the main surgeon (right) resects the tumor.

Figure 5. 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 6a. Standard endonasal approach. above, patient positioning; below left, endonasal hemitransfixion incision; below right, direct sphenoidotomy technique.

Figure 6b. Above, standard endonasal approach showing the trajectory to sella in sagittal view; below, sequential steps used in tumor removal and repair of the sellar floor common to all techniques.

Figure 7. Endoscopic views. A. After the anterior wall of the sphenoid sinus is opened, the endoscope provides a panoramic view of the sella and surrounding anatomy. B. Endoscopic view of the tumor bed after resection. C. Endoscopic view of the right cavernous sinus wall using the 0 degree endoscope. D. Note the dramatically improved view of the right cavernous sinus wall in the same patient using the 45 degree endoscope. (c= carotid artery)

Outcome

Visual deficits in patients with non-functioning pituitary adenomas are improved in approximately 87%. Some visual deterioration may occur in 4%. Most patients with intact pituitary function preoperatively retain their normal function. Those with preoperative pituitary deficiency regain function in 27% of the cases. The remaining patients are managed with oral hormone replacement therapy. Tumor recurrence is also higher. Ten-year recurrence rates are approximately 16%, although only 6% require additional treatment (Table 5). On long-term follow-up, 83% of patients are alive and well without evidence of disease.

Table 5. Results of Transsphenoidal Surgery, 1972-2000 (N=3093)
Tumor	Remission (%)	Recurrence at 10 years (%)
Non-functioning adenoma	Not applicable*	16
GH adenoma Microadenoma	88	1.3
Macroadenoma	65
PRL adenoma Microadenoma	87	13
Macroadenoma	56
ACTH adenoma Microadenoma	91	12 (Adults), 42 (Pediatric)
Macroadenoma	65
*Visual improvement occurs in 87% of those with preoperative visual loss.

Using strict criteria for remission, transsphenoidal surgery obtains remission in 72% 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.

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%.

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

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%. Larger invasive tumors and giant adenomas are associated with a higher morbidity.

Table 6. Complications of Transsphenoidal Surgery (1972-2000)
Outcome Measure	Incidence (%)
Mortality	<0.5
Majorcomplication: (CSF leak, meningitis,ischemicstroke, intracranialhemorrhage,vascular injury, visual loss)	1.5
Minor complication: (sinus disease, septal perforations, epistaxis, wound infections and hematomas)	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.

SUMMARY

The overwhelming majority of pituitary adenomas are benign and present either with characteristic syndromes of excess hormone secretion or secondary to mass effect by the growing tumor. The common hypersecretory syndromes include Cushing’s disease, Acromegaly/Gigantism, and Forbes-Albright syndrome. Local mass effect on the pituitary can cause varying degrees of hypopituitarism. As the tumor grows beyond the confines of the sella turcica, the visual pathways are commonly affected and cause 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