Principles and Practice of Endocrinology and Metabolism



Pituitary Tumors


Radiologic Evaluation

Surgical Approaches
Prolactin-Secreting Adenomas

Clinical Manifestations

Laboratory Evaluation

Surgical Decision Making

Vision Compromise in Prolactinoma

Prolactin-Producing Macroadenomas

Prolactin-Producing Microadenomas

Surgical Results

Endocrine Evaluation

Surgical Decision Making

Surgical Results
Cushing Disease

Endocrinologic Evaluation

Surgical Decision Making

Surgical Results

Preoperative Evaluation

Surgical Results
Endocrine-Inactive Pituitary Adenomas

Clinical Presentation

Surgical Results
Chapter References

Advances in endocrinology, neuroradiology, and microneuro-surgery have revolutionized the care of patients with pituitary and hypothalamic tumors. With the development of accurate radioimmunoassays and an understanding of the interactions between the hypothalamus and the pituitary, sophisticated endocrine testing can be performed to define the nature of the dysfunction precisely. Neuroradiologic techniques, particularly high-resolution magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), enable the clinician to localize many structural abnormalities to within 1 to 2 mm. Improvements in neurosurgical technology, including the use of the operating microscope, special microinstrumentation, and minimally invasive techniques such as endoscopy and high-resolution ultrasonography enable the surgeon to secure total removal of the lesion, with preservation of endocrine function and significant lowering of morbidity and mortality.
The differential diagnosis of lesions in the sella and hypothalamic region is vast. Two common lesions are considered in this chapter: pituitary adenomas and craniopharyngiomas (see also Chap. 11, Chap. 17 and Chap. 18).
The classic histologic designation of adenomas as chromophobic, eosinophilic, or basophilic on the basis of light microscopy is now obsolete and has been replaced by a system that classifies adenomas according to the hormones they secrete1 (see Chap. 11). The term chromophobe adenoma has been replaced by terminology that designates two types of nonsecreting tumors: the oncocytoma, which is thought to be a neoplasm with transformed epithelial cells without endocrine potential, and the null cell adenoma, which may have an as yet unidentified secretory product.2
Patients with tumors of the pituitary present for treatment either because of endocrinopathy or because of local mass effects. Classification according to the degree of sellar destruction (grade) and extrasellar extension (stage) can assist the physician in determining the surgical prognosis3 (Table 23-1).

TABLE 23-1. Anatomic (Radiographic and Operative) Classification of Pituitary Adenomas

Before MRI scanning reached its present level of sophistication, the diagnosis of a pituitary tumor was based on thin-section polytomography of the sella, pneumoencephalography, computed tomography (CT) scanning, and bilateral carotid angiography. MRI scanning with and without gadolinium enhancement, with magnified images obtained in the axial, coronal, and sagittal planes, has made pneumoencephalography, CT scanning, and polytomography obsolete because it can more accurately diagnose pituitary adenomas in most cases (see Chap. 20). An MRI diagnosis of adenoma is based on the fact that both normal pituitary gland tissue and the adjacent cavernous sinuses enhance at a different time after the administration of intravenous paramagnetic contrast material than does an adenoma, which often enhances poorly, and usually late.4 The timing of imaging is important. Most radiologists recommend imaging as soon as possible after the administration of the contrast. Other criteria suggestive of adenoma include a convex upper border of the pituitary gland (seen, however, in 2% of normal glands); increased height of the gland (>7 mm); lateral deviation of the pituitary stalk; and a focal area of altered attenuation relative to the normal gland, on either contrast or noncontrast studies. Usually, precise delineation between tumor and other important structures in the area can be accomplished (Fig. 23-1).

FIGURE 23-1. Magnetic resonance image without contrast (A) and with contrast (B) with direct coronal scans for a young woman with a pituitary macroprolactinoma. Note the low-density areas in the lesion on both scans. The surrounding tissue enhances after the administration of intravenous contrast, correlating well with the surgical finding of normal glandular tissue, rather than tumor, surrounding the low-density center. The tumor was precisely confined to the low-density area.

High-resolution MRI scanning with and without gadolinium enhancement is recommended for assessment of all suspected pituitary and hypothalamic lesions. Carotid angiography is reserved for those patients in whom an intrasellar aneurysm is suspected after high-quality MRI scans, including MRI angiography, have been performed. The author has not found it necessary to perform carotid angiography on the last 200 patients treated, now that high-resolution MRI angiography is available. CT scanning is no longer routinely performed in these patients. It can occasionally be helpful for patients in whom areas of hemorrhage, bony erosion, or calcification are being assessed or for patients with unusual bony sphenoid sinus anatomy, particularly those who have undergone previous transsphenoidal exploration.
Surgical approaches to pituitary adenomas have been described in detail.5,6 The specific morphologic configuration of the neoplasm, rather than the endocrinologic syndrome, determines the choice between the transcranial and the transsphenoidal approach. The transsphenoidal approach is the technique of choice for tumors that occupy the sella, whether or not any extension has occurred into the sphenoid sinus (Fig. 23-2, Fig. 23-3 and Fig. 23-4). Tumors with vertical suprasellar extension without significant lateral extension are also well treated with this approach. The advantage of the transsphenoidal approach is that it usually allows selective excision of tumor with preservation of remaining normal pituitary gland, even when most of the sella is occupied by tumor. The approach involves no retraction of the cortex whatsoever, as opposed to the transcranial approach, in which, at times, considerable brain retraction may be necessary. In addition, the morbidity of the procedure is exceedingly low, and it is well tolerated even by patients who would be considered unacceptable surgical candidates for craniotomy. In experienced hands, only 1% of patients with pituitary tumors require a transcranial operation.

FIGURE 23-2. Bony and cartilaginous anatomy of the base of the skull, sphenoid sinus, and nasal areas. Note that the posterior wall of the sphenoid sinus is the floor of the sella turcica, making the transsphenoidal route uniquely suited for the removal of sellar lesions. (From Tindall GT, Barrow DL. Disorders of the pituitary. St. Louis: CV Mosby, 1986.)

FIGURE 23-3. Diagrammatic summary of the transsphenoidal surgical approach. A, A linear incision is made from canine fossa to canine fossa. The entire surgical field lies within this incision. This provides a cosmetically favorable result because the scar is never visible externally. The nasal mucosa is dissected away from the cartilaginous and bony nasal septum. B, A speculum is then placed to expose the sphenoid sinus, and the posterior wall of the sphenoid sinus (the floor of the sella) is removed. Note the adenoma in the anterior aspect of the gland, where most of these lesions are located. This procedure is performed with the aid of an operating microscope, using a C-arm fluoroscope, which facilitates visualization of the area. C, Removal of the microadenoma. Using magnification and microdissection technique, the adenoma can be removed from the gland, sparing the normal gland tissue. D, Reconstitution of the sella after removal of the tumor or the gland. Fat is placed in the sella to prevent downward migration and herniation of the optic chiasm. A piece of nasal bone is then used to reconstitute the sellar floor, which later calcifies and forms new bone. (A, C, and D from Hardy J. Transsphenoidal operations on the pituitary. Codman and Shurtless, Inc. A division of Johnson and Johnson. 1983; B from Tindall GT, Barrow DL. Disorders of the pituitary. St. Louis, CV Mosby, 1986.)

FIGURE 23-4. Technical details relating to removal of a microadenoma. A, Basic principles of tumor removal. Note the development of a plane between the tumor located laterally and the normal gland located medially. B, Dissection of the pseudocapsule, or the fibrous tissue surrounding the outer aspects of the tumor, which ensures a clean removal. C, Two important principles of microsurgical removal are illustrated. The first is to carefully inspect, or at least palpate, all hidden pockets. One can see tumor hidden in the anterior corner of the sella, which is extracted by the inserted curette. In addition, extracting the surrounding tissue for biopsy to confirm that it contains only normal gland and, therefore, that all tumor has been removed is usually advisable. (From Hardy J. Transsphenoidal approach to the sella. In: Wilson CB, ed. Neurosurgical procedures: personal approaches to classical operations. Philadelphia: Williams & Wilkins, 1992:30.)

An advance in surgical technology is the introduction of endoscopy (Fig. 23-5) into neurosurgical procedures.6a In selected cases, a transsphenoidal resection can now be performed via one nostril using the endoscope, so that the degree of invasiveness of the operation is even further reduced.7 Moreover, the endoscope now permits the surgeon to “look around the corner” at angles that were not possible using conventional microsurgical techniques, thereby improving surgical outcome. Patients do not have nasal packing placed, which thus avoids both the numbness in the upper teeth that persists for at least several months and the nasal congestion and stuffiness that often occurs for several weeks after a standard transsphenoidal operation. In many cases, the patient can be discharged as early as the first postoperative day. A few patients have been given surgery on an outpatient basis with excellent outcomes.

FIGURE 23-5. The use of the endoscope for transsphenoidal surgery. A, Diagram demonstrating an endoscopic endonasal approach to a sellar tumor. No septal, alar, or gingival incision is used, and no speculum or retractor is necessary. B, The endoscope is held in the surgeon’s hand until an opening is made into the sphenoid sinus. C, The endoscope is mounted on a special holder, which provides the surgeon with a steady video image and frees both hands to use surgical instruments simultaneously. (From Jho HD, Carrau RL. Endoscopic endonasal transsphenoidal surgery: experience with 50 patients. J Neurosurg 1997; 87:44.)

Another advance is the refinement of intraoperative technology to permit the use of ultrasonography in the operating room to localize small tumors that might be otherwise difficult to visualize.8 This is particularly useful for patients with Cushing disease for whom imaging studies have been normal or equivocal. The ultrasonic probe developed for this procedure is pencil thin and can therefore be used in the very small area that constitutes the surgical field.
Prolactin-secreting adenomas comprise the largest group of pituitary tumors. The behavior and relatively benign clinical manifestations of small prolactinomas distinguish them from the tumors that produce Cushing disease and acromegaly, two distinct endocrinopathies that are usually life-threatening. Whereas the clinical necessity of treating patients with either Cushing disease or acromegaly is clear, the indications for immediate treatment of patients harboring a small prolactin-secreting adenoma are less so (see Chap. 13 and Chap. 21).
In 1954, Forbes and colleagues9 first reported that pituitary adenomas could produce amenorrhea and galactorrhea. However, only recently have these tumors been recognized as a frequent cause of secondary amenorrhea and galactorrhea. Among the women in one surgical series5 (Table 23-2), 80% presented with secondary amenorrhea or galactorrhea, 10% with primary amenorrhea, and 10% with either oligomenorrhea and galactorrhea, secondary amenorrhea without galactorrhea, or secondary amenorrhea only. Among men, prolactinomas usually remain undetected until a large tumor produces either significant panhypopituitarism or compression and invasion of the parasellar structures. In the previously mentioned series,5 only seven men had symptomatic hyperprolactinemia without abnormalities of additional pituitary hormones; either thyroid, adrenal, or gonadotropic function, or a combination of the three, was usually impaired as well. Many of these patients experience impotence early in the course of their disease, but this problem often does not lead to an investigation of the prolactin level. The author can recall seeing in his practice a 35-year-old man who received electroshock therapy for 10 years as “treatment” for his impotence; the patient presented with a prolactin level of >1000 ng/mL.

TABLE 23-2. Clinical Features of 121 Patients with Prolactinoma Treated by Transsphenoidal Surgery*

Hyperprolactinemia secondary to a pituitary adenoma has extragonadal manifestations. Recent rapid weight gain is a frequent complaint of hyperprolactinemic women and occurs with a frequency that suggests a correlation. Correction of hyperprolactinemia, either by surgery or by medical therapy, has been followed by impressive weight loss in many cases, despite no apparent change in dietary habits. Equally impressive is the incidence of emotional lability, which is often dramatically reversed after the correction of hyperprolactinemia. Studies demonstrate that the estrogen deficiency secondary to hyperprolactinemia causes bone demineralization, sometimes producing secondary complications.10
The first step in the evaluation of a patient with suspected hyperprolactinemia is to obtain a fasting serum prolactin level. The administration of thyrotropin-releasing hormone (TRH) does not consistently distinguish between functional hyperpro-lactinemia and actual prolactinoma11 (see Chap. 13). In men whose basal prolactin values exceed 100 ng/mL, establishing a prolactinoma as the cause of the hyperprolactinemia is not difficult. In women, hyperprolactinemia (>200 ng/mL) almost invariably indicates a tumor. Caution must be exercised, because prolactin levels as high as 662 ng/mL have been observed to occur in nonsecreting tumors, presumably due to pronounced pressure on the pituitary stalk, which inhibits the transport of prolactin inhibitory factor to the pituitary gland.12
In the author’s experience, the diagnosis of prolactinoma in a patient with basal prolactin levels <200 ng/mL requires radiographic identification of an intrasellar lesion. Even with unequivocal radiographic demonstration of such a lesion, transsphenoidal exploration occasionally reveals either a diffusely enlarged anterior lobe (pituitary hyperplasia) or a nonneoplastic intrasellar cyst, most often involving the pars intermedia. In such cases, the presence of the radiographic abnormality is usually not related to the elevated prolactin level. Patients must, therefore, be cautioned about this possibility, particularly now that the resolution of MRI imaging has become so good.
As experience with the use of the dopamine agonists (i.e., bromocriptine and cabergoline) accumulates, the indications for surgery in patients with prolactin-secreting tumors are changing. Currently, most patients who are referred for surgery have large and invasive tumors. Although a role exists for surgery in these patients, they are rarely cured by an operation alone, and usually require supplemental drug therapy, radiation therapy, or both.
The young and healthy patient with a microadenoma has an excellent chance to obtain a long-term remission with surgery; however, most are treated with medication and are never referred to a surgeon. In the author’s opinion, surgery has a role in the treatment of these patients, as long as they are properly counseled regarding the options of medical and surgical therapy, and the pros and cons of either approach. Surgery provides the possibility of cure, obviating the need to take medication for years or for the patient’s lifetime. Patients should be informed, however, that medical therapy is a perfectly acceptable treatment modality that in most cases provides adequate control of the tumor without the need for subsequent surgical intervention.
Many would agree that medical therapy (bromocriptine or cabergoline) is indicated for the management of prolactinomas that are of sufficient size and invasiveness to produce serum prolactin levels of >600 ng/mL. (For such lesions, the cure rate with surgery, even in the most experienced hands, is only 10%.10) Medical therapy is usually effective for long-term control, with normalization of serum prolactin levels. On the other hand, the presence of vision loss complicates the management of such patients. This is because of the concern that such therapy either may fail or may take too long to produce sufficient reduction of tumor volume to relieve the compression of the vision system, which could result in further irreversible vision damage during the trial of medical treatment. Because vision compromise can reverse after surgical treatment, even when the compression is longstanding, some believe that vision compromise is not a contraindication to a trial of medical therapy. Substantial tumor shrinkage can occur within days, leading to improved vision.13,14 Others,5,6 including the author, believe that surgical intervention is indicated in these patients if they are otherwise healthy, because a risk exists of further permanent vision damage with the less rapid decompression provided by medical therapy. If medical therapy is selected for patients with vision compromise, careful monitoring of vision is essential.13,14
For macroadenomas, operative removal is recommended if visual compromise is present and if the patient’s overall medical condition justifies the small risks of surgical intervention. For macroadenomas without compression of the optic apparatus, surgery may be considered if the tumor is <2 cm and the prolactin level is <600 ng/mL, because surgical cure and a low complication rate are reasonable expectations under these conditions.13 For tumors >2 cm and prolactin levels >600 ng/mL, medical therapy is recommended initially. A desire for pregnancy complicates matters, because pregnant patients with macroadenomas may develop complications related to accelerated tumor growth. Because of this concern, such patients may be candidates for surgery, even if no visual compromise is present.
For microadenomas, opinions differ among surgeons concerning initial treatment. Some believe that all patients should be treated medically, except for those who develop unacceptable side effects to medical therapy or whose tumors are resistant to dopamine agonists.15 Others believe that surgery should be the initial treatment for healthy patients with microadenomas and that bromocriptine, cabergoline, and irradiation should be reserved for cases of surgical failure or for those in whom the risk of surgery is high.5,6
Surgery does not always cure prolactin-producing microadenomas; in particular, tumors with higher prolactin levels have a greater likelihood of surgical treatment failure. Serious surgical complications can occur, although, in experienced hands, the complication rate is <1%. Still, medical management is not a perfect solution. Treatment with medication is a lifelong commitment. At effective doses, a significant number of patients have unpleasant side effects, although they may be able to tolerate these symptoms and continue to take the drug. Use of the dopamine agonist cabergoline has reduced some of the undesirable side effects associated with medical therapy. Some tumors are relatively resistant to bromocriptine, as indicated by either inadequate lowering of the prolactin levels or continued growth of the tumor. In such cases, the tumor may have a mixed population of cells, some of which are not responsive to bromocriptine (pseudoprolactinoma).16 Well-documented cases have been seen of progressive enlargement of pituitary tumors, pituitary apoplexy, and even metastases of adenomas during bromocriptine therapy.17,18 and 19 If nonsurgical management is chosen, a progressive elevation in prolactin levels approaching 200 ng/mL, or an enlargement of the tumor detected on MRI, represents a secondary indication for surgical intervention. Some believe that long-term treatment with medical therapy reduces the success of subsequent surgery; this effect has been reported to be due to the perivascular fibrosis that occurs when the tumor shrinks during drug treatment.20
The surgical treatment of prolactin-secreting microadenomas results in a remission rate of 72% to 97%.21,22,23,24 and 25 Remissions were experienced by 88% of patients who had preoperative prolactin levels of <100 ng/mL, whereas 50% of patients with prolactin levels of >100 ng/mL experienced remissions.25 In long-term studies, remissions were observed in 93% of patients with microadenomas as well as in 88% of patients with tumors (regardless of size) confined to the sella or extending only moderately into the suprasellar region.5 By contrast, remissions were seen in only 37% of female patients and in 15% of male patients who had significant extrasellar extension of tumor and were treated with surgery alone. In a series of patients receiving surgery for microprolactinoma who were followed for a mean of 70 months, only a 3% recurrence was observed.22 Moreover, beyond 10 years after surgery, the cost of medical therapy exceeds that of surgery.
The value of surgery in treating macroadenomas without chiasmal compression in patients who have no special circumstances such as a desire for or presence of pregnancy, medication intolerance, or poor response to dopamine agonists is questionable. Surgery combined with dopamine agonists has been compared to use of dopamine agonists alone in the long-term treatment of macroprolactinomas.23 Clearly, for this group of patients surgery did not improve the ultimate outcome for patients who responded to dopamine agonists. The situation is quite different for microadenomas. A study of surgery for microadenomas at an experienced center indicates a remission rate of 84%, even in patients followed for a median of 15.6 years. A 97% remission rate was seen in patients who received surgery using an improved microsurgical technique at a mean follow-up of 3.2 years.24
Even when the procedure is performed by experienced surgeons, prolactinomas have a higher recurrence rate than that of any other pituitary adenoma after primary successful surgery. Recurrence rates vary from 14% to 50% in published series26,27 (Table 23-3). In part, the high recurrence rate may arise from the cause of the prolactin-secreting tumor, which is related to hypothalamic dysregulation. This dysregulation is unaltered after total resection of neoplasm, which leads to the growth of a new tumor rather than regrowth of residual tumor cells. In the author’s experience, serum prolactin levels measured in the early postoperative period have prognostic value. A value of <5 ng/mL virtually assures a cure, whereas a prolactin level of >15 ng/mL is presumptive evidence of residual tumor and implies a probable regrowth.

TABLE 23-3. Recurrences after Transsphenoidal Surgery for Prolactinomas: A Survey of the Recent Literature

By the time a patient with a growth hormone (GH)–secreting pituitary adenoma seeks the advice of a neurosurgeon, the diagnosis is usually obvious, and the need for therapy is urgent. Left untreated, this type of tumor produces metabolic disturbances with deleterious consequences and is associated with increased mortality.
The surgical options for the treatment of GH-secreting pituitary tumors include craniotomy or transsphenoidal surgery,28,29 either for removal of the entire pituitary gland or for selective removal of adenomatous tissue. Irradiation, first used for the treatment of acromegaly in 1909, still provides an alternative to surgical intervention (see Chap. 22).
The evaluation of a patient with suspected acromegaly begins with a determination of the fasting GH level along with a complete assessment of anterior pituitary function (see Chap. 17). Additional testing should include the measurement of serum insulin-like growth factor-I (IGF-I, somatomedin C). Failure of suppression of GH levels to ❤ ng/mL after oral administration of glucose can be helpful diagnostically, especially in patients with normal fasting GH or IGF-I levels who appear to be clinically symptomatic. A paradoxical rise in GH levels is seen after the intravenous administration of TRH in half of the patients. This test can be included in the preoperative evaluation.
First-line therapy for patients with acromegaly should be transsphenoidal surgery, especially if a microadenoma or small macroadenoma without invasion of the cavernous sinus is present.30 Medical therapy as a primary treatment modality should be reserved for those in whom surgery cannot be safely undertaken.
In the postoperative evaluation of the patient with acromegaly, the goals are a fasting GH level of <5 ng/mL and normalization of the IGF-I level. The restoration of normal GH dynamics, with a glucose-induced suppression of the serum GH level to ❤ ng/mL after an oral glucose load, is desirable; however, in the author’s experience, the absence of such normalization does not necessarily imply residual tumor or recurrence. Importantly, normalization of GH and IGF-I levels may first occur as long as 3 to 6 months after surgery. Thus, if these values are elevated in the immediate postoperative period, a failure of surgery is not inevitable.
In experienced hands, transsphenoidal surgery is a highly effective treatment for the GH-secreting pituitary adenoma. Among 103 patients who underwent surgery during a 17-year period, the overall success rate of surgery alone was 82.4% in previously untreated patients, compared with 75% in patients with prior bromocriptine therapy and 63.6% in patients with prior radiation therapy.31 Tumor stage was a strong predictor of outcome, with greater suprasellar extension associated with less favorable results. The tumor grade and the preoperative GH and IGF-I levels were also significant predictors of surgical success, with higher grade and higher preoperative serum hormonal levels associated with a less favorable outcome. In a study of 175 patients treated by transsphenoidal surgery during a period of 11 years, probability of remission after 5 years was 62.7%.32 Moreover, the tumor size and the preoperative basal GH level correlated with outcome; a larger tumor size and a higher GH level were associated with less favorable results. Findings from the University of California in San Francisco28,29 demonstrated long-term remission rates ranging from 80% to 90%, depending on the exact biochemical criteria used. Suprasellar extension, higher preoperative GH levels, and higher grade and stage also correlated with a less favorable outcome. Similar results were reported in another study,33 which noted a 78% cure rate for enclosed adenomas in 100 acromegalic patients. This finding has been supported by a long-term study34 in which patients were followed for at least 5 years. The cure rate for microadenomas was 88%. Similar results have been reported elsewhere with a long-term remission of 83%.35
Some authors have concluded that early postoperative GH dynamics do not clearly correlate with either long-term cure or recurrence. Thus, recurrence of acromegaly has been reported in three patients with normal postoperative GH dynamics.36 Others have found that, although not all patients who have normal early postoperative GH levels but exhibit abnormal dynamics eventually experience relapse, such patients are nevertheless more likely to relapse than those who experience a complete biochemical remission.
Clearly the recurrence rate for acromegalic patients after selective adenomectomy is much lower than the rate that has been reported for prolactinomas. Although the reasons are not entirely clear, the suggestion has been made that most GH-secreting adenomas arise de novo in the pituitary gland and are not the result of underlying hypothalamic dysregulation. Table 23-4 summarizes reported recurrence rates seen after transsphenoidal surgery for acromegaly. Reoperation in these patients is successful in 88% if the MRI scan demonstrates a focal tumor recurrence within the sella.37 Note that, for the endocrine-active tumors, the results of surgery are best in these circumstances.

TABLE 23-4. Recurrences after Transsphenoidal Surgery for Acromegaly: A Survey of the Recent Literature

Although radiation therapy is highly effective as adjunctive treatment in patients with GH-secreting adenomas, its value as a primary therapeutic modality is less clear. A comparison of response rates indicates that the results obtained with transsphenoidal surgery are superior to those obtained with irradiation alone. Moreover, the response to transsphenoidal surgery is immediate, whereas a period of several years after the completion of radiation therapy is required before remission is obtained. During this time, the metabolic abnormalities associated with acromegaly continue unabated. Bromocriptine may be a useful adjunct in the treatment of some GH-secreting tumors, but except in rare cases, it is not effective as a primary mode of therapy19 (see Chap. 21). The results of the International Multicenter Acromegaly Study Group using the somatostatin analog octreotide38 do not compare favorably with the results of surgery. Although 88% of patients did show reduction in serum GH and IGF-I levels associated with clinical improvement, strict criteria used to define biochemical cure after surgery were met in less than half of the patients. Furthermore, unlike in the treatment of prolactinomas with bromocriptine, only 44% of patients treated with octreotide showed a decrease of tumor size, and only by 20%. Surgical results have been compared with octreotide treatment results in a series of patients who were first treated medically and then underwent surgery.39 The effects on the levels of high-affinity GH–binding protein, GH, IGF-I, and insulin-like growth factor–binding protein-3 were determined. These markers did not normalize with octreotide therapy but did normalize after surgical removal of the tumor. Therefore, although somatostatin analogs hold promise for the future, they are presently indicated only as adjunctive treatment for patients for whom surgery, radiation therapy, or both have failed (see Chap. 169).
Of the therapeutic modalities available for the treatment of GH-secreting pituitary adenomas, only transsphenoidal surgery offers the unique combination of a low morbidity rate, a low incidence of postoperative hypopituitarism, and immediate remission.
Cushing disease has fascinated neurosurgeons ever since Harvey Cushing described the clinical syndrome and predicted that one cause of the disorder was a small pituitary adenoma.40
No endocrinologic findings yield a 100% accuracy rate in the diagnosis of Cushing disease. The evaluation of patients suspected of having this condition should start with verification of sustained hypercortisolism. Morning and evening levels of serum cortisol as well as a 24-hour urine collection with measurement of urinary free cortisol levels should be determined. The diagnosis can generally be established by the demonstration of nonsuppressibility of corticosteroids in serum or urine after administration of low-dose dexamethasone but at least 50% suppressibility after administration of high-dose (8 mg) dexamethasone. A lack of suppression with high-dose dexamethasone can be seen in cases of macroadenoma and thus does not necessarily rule out an adrenocorticotropic hormone (ACTH)–secreting adenoma.41 An elevated serum ACTH level in the presence of hypercortisolism provides additional supportive evidence.
Percutaneous transfemoral selective inferior petrosal venous sampling for ACTH before and after the administration of corticotropin-releasing factor has also been of help in equivocal cases.42 If the diagnosis is uncertain and a paraneoplastic (“ectopic”) source of ACTH secretion is suggested, selective venous sampling to determine a cephalic plasma ACTH gradient has proved to be diagnostically definitive.5 When the samples have been obtained from the inferior petrosal sinus, no misleading results have been found. Sampling of another pituitary hormone along with ACTH is helpful to reduce confusion about results from various sites (see Chap. 74, Chap. 75 and Chap. 219). Such sampling can be taken directly from the cavernous sinus, using a superselective microcatheterization technique.43
Experience indicates a high likelihood of cure after surgery if the serum cortisol values, measured at 8:00 a.m. and at least 24 hours after discontinuation of oral hydrocortisone therapy, either are unmeasurable or, if they are within the normal range, are shown to suppress fully during low-dose dexamethasone testing.44,45 and 46 Some investigators have reported that Cushing disease has not recurred in any patient with undetectable serum cortisol in the early postoperative period,44 although a normal cortisol level during this time does not necessarily imply failure. Measurement of ACTH levels during the operation does not accurately predict complete tumor resection.47
Like patients with acromegaly, patients with Cushing disease require swift and efficacious therapeutic intervention (i.e., selective pituitary adenectomy). In adults, a total hypophysectomy is recommended if no abnormal tissue is identified during the transsphenoidal exploration. If no tumor is found in a child or in a young adult, postoperative radiation therapy or medical therapy is recommended instead of hypophysectomy. The rationale for this approach is that panhypopituitarism excludes procreation (except in rare cases after gonadotropin therapy) and that, even with synthetic GH, severe growth limitations occur in children.
Once the pituitary has been established as the cause of a patient’s hypercortisolism, the treatment of choice is transsphenoidal exploration. Patients who have negative imaging studies require careful systematic exploration of the intrasellar contents by an experienced pituitary surgeon.48 Microadenomas secreting ACTH can often be small and located deep within the gland, so that the tumor is not immediately visualized when the dura is opened. Experience with systematic exploration, including microsurgical dissection and the ability to visualize areas that are technically difficult to reach, is essential to achieve optimal surgical results.49 Although false localizing results that were based on sampling of the inferior petrosal sinus have been described, the author always first explores the side with the higher gradient in patients with negative imaging studies and no obvious tumor. In most cases, such exploration has been fruitful.
The results of surgical exploration in experienced hands are good, with remission rates ranging from 75% to 92%.50,51,52 and 53 In a large surgical series, an 86% long-term remission rate was achieved for adenomas confined to the intrasellar compartment, whereas only 46% of patients were successfully treated once the tumors had extrasellar extension.50 Similarly, the recurrence rate was only 1.2% in those with intrasellar adenomas, whereas it was 15% in those with extrasellar adenomas. A high grade and stage of the tumor were associated with a low initial remission and a high recurrence rate. The results of this series are summarized in Table 23-5.

TABLE 23-5. Surgical Outcome in Relation to Tumor Size, Extension, and Histologic Confirmation in 216 Patients with Cushing Disease

Unlike with other endocrine-active tumors, in 10% to 15% of patients with a preoperative diagnosis of Cushing disease, no tumor is found, even in the most experienced surgical hands. Some of these patients later are discovered to have paraneoplastic (ectopic) tumors, whereas others may be discovered to have a more obvious pituitary adenoma. Another small subgroup has an entity known as pituitary hyperplasia (hyperplasia of ACTH-secreting cells without obvious neoplasm). Such patients are candidates for either total hypophysectomy or, later, surgical (or medical) adrenalectomy. Pituitary irradiation also may be considered if the pituitary exploration does not reveal an adenoma. The final decision must be individualized. Young patients who desire pregnancy probably are better served by adrenalectomy, despite the risk of subsequent Nelson syndrome. Patients in whom the ability to conceive is not an issue and for whom total endocrine replacement does not produce an excessive burden are better served by total hypophysectomy.
In patients with ACTH-secreting pituitary adenomas, the recurrence rate ranges from 3% to 15% for the most experienced surgeons (Table 23-6). As with prolactin- and GH-secreting tumors, the most significant factor contributing to surgical failure is suprasellar or extrasellar extension of tumor. The absolute level of serum ACTH has not proved to be as reliable a prognostic indicator as are the prolactin or GH levels for the previously discussed adenomas. This may be attributed to variability in the values obtained with the radioimmunoassay for ACTH. Considering the morbidity and mortality associated with this disease, surgical treatment is a reasonable option.

TABLE 23-6. Recurrences after Transsphenoidal Surgery for Cushing Disease

Craniopharyngiomas have challenged neurologists and neurosurgeons since these tumors were first described in 1903.54 With advances in microsurgical technique, the thought was that the total removal of these lesions would be achieved more readily. Although the results of such surgery have improved, most surgeons continue to find this procedure extremely difficult and fraught with morbidity and mortality. Subtotal removal often is the best that can be achieved, even with advanced microsurgical technology and superlative surgical skill.55 Considerable debate exists about the surgical philosophy regarding craniopharyngioma: radical total removal in most cases versus a procedure that is more conservative and attempts to remove as much tumor as is possible, with the surgeon terminating the procedure when dense adherence to important neural or vascular structures is encountered. The problem is further complicated by the fact that adult and childhood craniopharyngiomas probably are different in this regard. That is, total removal is more easily achieved in children because the tumor has been present for a shorter period of time and, therefore, produces less inflammatory and gliotic reaction. In some cases total removal can be achieved with minimal morbidity, whereas in others such removal is not possible without damaging surrounding vital structures. Some of these neoplasms are densely adherent to the optic nerves, hypothalamus, and internal carotid artery; in these cases, an aggressive approach can produce a devastating outcome, even in the most experienced hands.
Radiation therapy plays an important adjunctive role in the treatment of this lesion. The MRI scan has been beneficial in resolving the controversy concerning which patients should undergo radiation therapy. Those patients with residual or recurrent tumor usually can be distinguished from those who have a clean surgical removal. Surgical intervention plus radiation therapy yield superior results compared with surgery alone in patients with obvious recurrent or residual tumor. This may be because the cells producing the secretions that form the cyst of this tumor have their secretory character altered by therapy. Therefore, radiation therapy is mandatory for optimal treatment of most incompletely removed tumors (see Chap. 22).
Unlike pituitary adenomas, many craniopharyngiomas require a transcranial approach because most of these lesions are located in the suprasellar region and often do not even extend into the sella. Furthermore, many of these tumors have a dense gliotic scar around them, which makes delivery of the suprasellar component of the tumor into the sella difficult without producing unacceptable damage to the suprasellar structures, including the hypothalamus and/or the optic apparatus. A transsphenoidal approach can be performed in a minority of patients, usually those in whom the tumor is confined largely to the sella. In these patients, the outcome is good, with less morbidity and frequent total tumor removal.56,57
A complete assessment of the hypothalamic-pituitary axis is required for patients with a craniopharyngioma because often significant hypofunction of one or more of the pituitary hormones is present. Unlike with the pituitary adenomas, diabetes insipidus may be a presenting symptom for which patients should be evaluated.
Detailed assessment of visual function is critical. These tumors tend to be regionalized to the optic nerve, chiasm, and tract, and significant defects in visual function are common58 (see Chap. 19).
In 61 children with craniopharyngiomas who were treated with radiation therapy, surgery, or both, the addition of radiation therapy to surgical treatment or the use of radiation therapy alone provided a higher likelihood of regression of disease than did surgery alone.59 In a study of 27 patients, total resection with no recurrence was achieved in 10 patients.60 A 7% recurrence rate was reported among 144 patients, of whom 90% had complete resections.61 Most of 173 patients treated at the Royal Marsden Hospital underwent incomplete or partial excision followed by treatment with radiation therapy.62 The 10- and 20-year progression-free survival rates were 83% and 79%, respectively, supporting the concept that subtotal removal and radiation therapy can achieve excellent long-term tumor control and patient survival with low morbidity. In a series of 168 consecutive patients undergoing surgery between 1983 and 1997, total tumor removal was achieved in 45%.57 Even with this modest attempt at total removal, mortality was 1.1% in primary cases and 10.5% in cases of tumor recurrence. No patient who underwent transsphenoidal surgery died. The rate of recurrence-free survival after total removal was 86% at 5 years and 81% at 10 years. The authors concluded that total tumor removal was preferable, but this was not always possible without hazardous intraoperative manipulation.
In a retrospective analysis63 evaluating the neurologic and behavioral sequelae in 32 patients who underwent surgery, total excision was associated with greater immediate mortality and morbidity as well as a higher incidence of subsequent behavioral disability. In a series55 of 74 patients with craniopharyngiomas treated during a 15-year period, an attempt was made to achieve a total removal. When this could not be achieved, the patients were treated with postoperative irradiation. Total removal was achieved in seven patients, six of whom have had no recurrence. However, of the entire series, 91% of treated patients were in long-term remission and fully functional.
Although total removal of a craniopharyngioma is possible in some patients in the adult population, this cannot always be achieved. A subtotal removal of tumor followed by radiation therapy has proved to be a satisfactory approach and has led to remission in most patients. With continued careful endocrine replacement therapy and monitoring, these patients can resume a normal functional life.
Endocrine-inactive pituitary adenomas produce clinical effects only as a direct consequence of their growth. Resulting clinical syndromes reflect either damage to the anterior pituitary gland and subsequent hypopituitarism, or compression of suprasellar and parasellar structures with development of associated neurologic deficits. Although these tumors have the necessary genetic information and cytoplasmic organelles to manufacture hormones and subunits, the products are secreted either in subclinical concentrations or in bioinactive forms; thus, these neoplasms are termed endocrine-inactive. When immunocytochemical and electron microscopic characteristics are taken into consideration, these tumors can be divided into null cell adenomas, oncocytomas, and glycoprotein-secreting adenomas.64
Patients with endocrine-inactive pituitary adenomas generally present with visual impairment or hypopituitarism. Headaches are common and can be severe, relating to dural pressure. A variety of visual field defects can be seen, the most common being bitemporal hemianopia or bitemporal superior quadrantanopia. Extraocular dysfunction, related to lateral growth into the cavernous sinus, can occur, with consequent compression of the oculomotor, trochlear, or abducens nerves. Dementia and other symptoms associated with hydrocephalus also can occur when these tumors compress the third ventricular outflow, producing obstructive hydrocephalus.
These neoplasms can occasionally occur in children and adolescents. Presenting symptoms differ and usually include pubertal and growth delay and/or primary amenorrhea.65 The tumor characteristics in this group of patients do not differ from those in the adult population.
Surgical resection of these adenomas does not differ appreciably from the surgery for endocrine-active tumors, except that the tumors are more likely to be macroadenomas, with higher grades and stages. This results in a lower cure rate with surgery alone, which is related to size and extrasellar extension rather than to any innate biologic difference.
The goals of surgery include establishment of a diagnosis, decompression of adjacent structures, and an attempt at total surgical removal. Seventy-five percent to 80% of patients with visual compromise experience significant recovery of vision after transsphenoidal resection. Cure rates are low, ranging from 20% to 30%.64 Although some recommend postoperative radiation therapy in all patients because of the low cure rate, others recommend careful serial MRI scanning, with radiation therapy reserved until obvious evidence is found of tumor regrowth. In support of the former approach is the reported 21% recurrence rate in a series of 126 patients with endocrine-inactive adenomas. All of these tumors except one were macroadenomas.66
Glycoprotein-secreting adenomas that may be associated with clinical symptoms (those producing thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone) are discussed in Chapter 15, Chapter 16 and Chapter 42.
In contrast to the results obtained in the past, the outcome of neurosurgical intervention for pituitary and hypothalamic neoplasms has improved greatly, due to both improvements in surgical technique and the use of the surgical microscope along with specialized microinstrumentation. In most cases, the disabling and often life-threatening consequences of disease in this area can be improved significantly by surgical intervention. For pituitary adenomas, the development of the transsphenoidal technique and its subsequent refinement using endoscopy (see Fig. 23-5) and high-resolution ultrasonography has converted an operation with major morbidity and mortality into one with few complications and very good results.

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