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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 82Pituitary Neoplasms

, MD and , MD.

The classic histologic designation of pituitary neoplasms as chromophobic, eosinophilic, or basophilic, based on their histologic appearance as seen with light microscopy,1 has been superseded by a system derived from the work of Landolt2 and Kovacs et al.3,4 in which the adenomas are classified according to the hormone(s) they secrete (Table 82.1).1–4 Pituitary neoplasms are generally considered either active or inactive from an endocrine standpoint. They are endocrine-active only if they secrete enough biologically active hormone to exceed normal levels in the blood and become clinically evident. Endocrine-inactive adenomas, in contrast, contain secretory granules and the cellular constituents for hormone production2 but either produce normal hormone in undetectable amounts or secrete abnormal hormone that is not recognized by the antibodies used in radioimmunoassays, or they have lost the ability to produce hormone through de-differentiation or degeneration. Molecular biology should ultimately yield an even more informative classification of pituitary tumors. Evidence has disclosed a monoclonal origin of most adenomas, implying that a somatic mutation of a single cell is likely to be the event initiating both hormone hypersecretion and neoplastic transformation.5,6 Two subsets of growth hormone (GH)-secreting adenomas have already been identified.7–9 A large percentage of patients with acromegaly bear somatic mutations in the α chain of the G protein (Gs) regulating the hormone-stimulatory activity of adenyl cyclase.10 The adenomas with the gsp mutation are significantly smaller than those without the mutation and are more sensitive to inhibitory factors such as somatostatin and dopamine—a characteristic that may prove to have therapeutic and diagnostic importance.

Table 82.1. Current Morphologic Classification of Pituitary Adenomas.

Table 82.1

Current Morphologic Classification of Pituitary Adenomas.

The adenoma’s local growth characteristics and size, irrespective of endocrine activity, predict its non-endocrine clinical presentation.11,12 Wilson’s anatomic (radiographic and operative) scheme,12–14 derived from Hardy’s,11,15 classifying pituitary adenomas by the degree of sellar destruction (grade) and extrasellar extension (stage), is valuable in establishing a prognosis and helpful in designing therapy. The following generalizations provide a framework for discussion of the more prevalent pituitary neoplasms.

For patients suspected of or known to be harboring a pituitary adenoma, the diagnostic imaging procedure of choice is magnetic resonance (MR) imaging (see Figs. 82.1 and 82.2). Gadolinium enhancement should be used for microadenomas (less than 10 mm in diameter) to help demonstrate the tumor.16 Although optional for macroadenomas, gadolinium administration can help to visualize the compressed pituitary gland and to differentiate between tumor and surrounding structures.17 T1-weighted images are preferably obtained using a 1.5 tesla MR imager with thin sections in coronal and sagittal planes.14 Whereas adenomas that secrete GH or adrenocorticotropic hormone (ACTH) can be predicted with virtual certainty on the basis of laboratory findings alone, a confident preoperative diagnosis of a prolactin (PRL)-secreting neoplasm requires radiographic evaluation as well.

Figure 82.1. A 55 year-old male with fatigue, decreasing libido, and bitemporal hemanopsia.

Figure 82.1

A 55 year-old male with fatigue, decreasing libido, and bitemporal hemanopsia. A. Coronal pre-contrast T1-weighted MR image (TR 600 milliseconds, TE 20 milliseconds) demonstrates a sellar mass consistent with a pituitary macroadenoma (A) that displaces (more...)

Figure 82.2. A 27 year-old woman with the recent onset of amenorrhea and galactorrhea.

Figure 82.2

A 27 year-old woman with the recent onset of amenorrhea and galactorrhea. A protactin level was elevated at 94. A. Coronal T1- weighted image before contrast demonstrates a focal low-density mass lesion in the left aspect of the pituitary gland adjacent (more...)

The transsphenoidal approach is the preferred surgical technique for almost all pituitary adenomas and the treatment of choice for those secreting GH (acromegaly) or ACTH (Cushing’s disease or Nelson’s syndrome). This approach is also preferred for certain nonsecreting tumors that extend out of the sella to compress adjacent structures and produce clinical manifestations, such as impaired vision. The operative approaches to pituitary adenomas have been described elsewhere.13,14,18 The objectives of surgery are to eliminate any mass effect of the tumor, to halt endocrine hyperactivity, to retain or improve existing pituitary function,19 to achieve these goals immediately and with minimal morbidity, and to predict accurately the need for adjuvant therapy.20 As yet, no widely accepted quantitative assay exists to aid in the estimation of an adenoma’s growth characteristics, but recent work has focused on the higher degree of expression of certain markers of cell growth (e.g., Ki-67 and p53) in invasive versus noninvasive adenomas.21,22 These markers may ultimately facilitate decision making regarding the use of postoperative adjuvant therapy and surveillance laboratory testing and imaging.

Whether the initial treatment for PRL-secreting adenomas should be medical or surgical, with bromocriptine or irradiation reserved for surgical failures, remains the subject of debate. For the rare and aggressive tumors secreting thyroid-stimulating hormone, the role and timing of surgery are unclear. An endocrine-inactive tumor in an asymptomatic patient with unimpaired pituitary function should, with some exceptions, be left alone and its course observed with serial MR images. Less well defined is the most effective management for pituitary apoplexy, the symptom complex that evolves acutely or subacutely as a consequence of hemorrhage and necrosis within an adenoma. At the University of California, San Francisco (UCSF), we tend to prepare the patient quickly and proceed directly with transsphenoidal surgery. If hypopituitarism is treated with suitable replacement therapy, but no surgery, the compressive symptoms may resolve in time, but the tumor will almost certainly require treatment at a later date. Medical management does not spare the patient an operation; it merely postpones it. The only exceptions are in some cases of PRL-secreting adenomas.14


PRL-secreting adenomas are the most prevalent pituitary adenomas. The behavior and benign clinical manifestations of small prolactinomas distinguish them from the adenomas that produce Cushing’s disease and acromegaly, two distinct metabolic entities that have severe and eventually fatal consequences independent of their effects as a mass. Unlike those lesions, prolactinomas manifest differently in men and women. Whereas large prolactinomas are slightly more prevalent in women than in men, men rarely present with microadenomas.


The level of PRL in serum, taken as an index of secretory activity, correlates directly with the size of the prolactinoma, exclusive of bulk contributed by necrosis and cysts. Necrosis is a common surgical finding in prolactinomas of all sizes. Prolactinomas, with rare exceptions, grow slowly.14

Clinical Presentation

Prolactinomas may produce primary23 or secondary amenorrhea and galactorrhea. The frequency of hyperprolactinemia in amenorrheic women is now well recognized. Equally evident is that prolactinomas are a common cause of hyperprolactinemia. Among women with prolactinomas treated at UCSF over 2 decades,14 80% had secondary amenorrhea and spontaneous or expressible galactorrhea; 10% had primary amenorrhea, one half of whom also had galactorrhea; and 10% had oligomenorrhea with galactorrhea, secondary amenorrhea without galactorrhea, or secondary amenorrhea only. In men, a prolactinoma usually goes undetected during the initial phase of hyperprolactinemia and the diagnosis may be established only after the adenoma has become large and caused significant hypopituitarism or compressed or invaded parasellar structures; a history of lessened libido, and eventually impotence, often precedes clinical manifestations of a large mass.

Hyperprolactinemia may have extragonadal manifestations, although possibly only in patients predisposed to these disorders. A recent, rapid, often excessive weight gain is reported by hyperprolactinemic women with a frequency that suggests a relation. Correction of hyperprolactinemia through surgery or bromocriptine therapy is in some cases followed by impressive weight loss despite no change in dietary habits. Equally impressive is the incidence of emotional lability and its reversal after correction of hyperprolactinemia. Obesity and emotional instability may reflect multiple non-endocrine factors, but hyperprolactinemia that is neither extreme nor longstanding also causes significant demineralization of bone, with its potential morbidity.24,25


A confident preoperative diagnosis of prolactinoma requires radiographic evidence of an intrasellar tumor unless serum PRL levels exceed 200 ng/mL; even with unequivocal radiographic demonstration of a pathologic abnormality in the pituitary gland, transsphenoidal explorations have in some cases revealed either a diffusely enlarged anterior lobe (pituitary “hyperplasia”) or a non-neoplastic cyst, usually in the pars intermedia.14 Attempts to distinguish functional or non-neoplastic hyperprolactinemia from the hyperprolactinemia produced by prolactinomas on the basis of laboratory values alone have yielded conflicting results. No single test or combination of tests is infallible. In men, with basal PRL values over 100 ng/mL, a prolactinoma is almost always the cause of hyperprolactinemia. In women, hyperprolactinemia and basal values over 200 ng/mL almost always indicate a prolactinoma; with some exceptions, basal values of 100 to 200 ng/mL have nearly the same significance. Women with basal levels of 50 to 100 ng/mL, termed moderate hyperprolactinemia, present a quandary. Values in this range may have no recognized cause, and a confident prediction of a prolactinoma cannot be based solely on laboratory values in women whose moderate hyperprolactinemia is unrelated to medication, pregnancy, or hypothyroidism. In a few patients, moderate hyperprolactinemia is the result of a stalk section effect produced by a readily identified pathologic intrasellar or suprasellar lesion, usually an endocrine-inactive adenoma or infrequently a suprasellar tumor such as a craniopharyngioma26 that interferes with downward blood flow through the pituitary stalk.


Unlike long-term medical therapy for Cushing’s disease and acromegaly, which is relatively ineffective, bromocriptine corrects the biochemical pathology of prolactinomas and reduces their size, at times dramatically. One view is that medical therapy should be used for all patients except the 30% or so who have unacceptable side effects from the medication.27 Fueling this view has been the wide variation in reported rates of recurrent hyperprolactinemia following surgery, ranging from 26 to 50%.28 In contrast is the opinion that surgery should be the initial treatment, with bromocriptine or irradiation reserved for patients who do not experience postoperative remission. 29,30 Although some clinicians question the wisdom of treating these patients at all, the potential for adverse systemic and psychological effects from hyperprolactinemia, and the potential for invasive behavior of the tumor provide compelling arguments for treatment, whether surgical or nonsurgical. The middle ground therefore seems preferable. Surgery does not predictably cure these adenomas, and the higher the patient’s PRL level, the greater is the potential for therapeutic failure. Moreover, serious surgical complications may occur, although with an experienced surgeon, the likelihood is no more than 1%. Medical management is hardly a perfect solution, either. It appears that medication must be a lifetime commitment for most if not all of the patients, a significant portion of whom have unpleasant side effects, and between 5 and 12% cannot tolerate bromocriptine at effective dose levels.31 A few tumors are relatively resistant to bromocriptine as judged by insufficiently lowered PRL levels and, in some cases, continued tumor growth.32 Finally, patients with macroadenomas who become pregnant may develop complications from accelerated tumor growth. Although treatment with bromocriptine usually resolves the problem, it may not.33,34

The low morbidity rates, the low incidence of recurrence, and the high likelihood of cure associated with selective transsphenoidal microsurgery support its use as the treatment of choice for patients with microprolactinomas. Of 219 women treated at UCSF for prolactinomas between 1976 and 1992,30 initial remission following surgery was achieved by 92% in those with preoperative PRL levels of ≤ 100 ng/mL and in 80 to 91% of those with microadenomas or noninvasive macroadenomas. With a median follow-up period of 15.6 years, 84% of women remained in clinical remission at latest evaluation. In contrast, only 37% of women with preoperative PRL levels of > 200 ng/mL and 30% with invasive adenomas experienced initial remission. The postoperative PRL level was the best predictor of continued remission, but patient age and adenoma stage were also significant. In this series, there were no deaths linked to surgical treatment, and only a 3% incidence of complications (cerebrospinal fluid [CSF] leak, meningitis, and hemorrhage), none of which resulted in permanent sequelae.

In patients with large, invasive tumors and extremely high PRL levels, the administration of a dopamine agonist, such as bromocriptine, either alone or in combination with surgery, pituitary irradiation, or both, appears to be the appropriate mode of therapy.35 Unless an MR image shows unequivocal invasion of the cavernous sinus, surgical cure is a reasonable expectation in any patient with a PRL level of 500 ng/mL or less.36 The lower the PRL level, the greater the likelihood of cure. The younger the patient, the clearer are the advantages of surgery and the less desirable is medical management. Patients who cannot tolerate medication become surgical candidates, with varying expectations of cure. Irradiation sterilizes but does not inactivate prolactinomas and is reserved for patients who are not cured by surgery and cannot tolerate medication.37


The policies currently determining recommended management at UCSF reflect our favorable experience with the microsurgical approach,30 the assumption that most prolactinomas grow relatively slowly, and the evidence that surgical treatment is less successful in patients with higher PRL values and tumor stage.30 These recommendations apply for the cases in which the clinical presentation, laboratory data, and the MR images eliminate any reasonable doubt that the patient harbors a prolactinoma.

Operative removal is recommended for most macroadenomas, virtually all of which are accompanied by PRL values > 100 ng/ml. Surgical remission is most likely for patients with PRL levels of ≤ 200 ng/mL and a microadenoma or a noninvasive macroadenoma. For noninvasive tumors larger than 2 cm, preliminary treatment with bromocriptine should reduce tumor volume and increase the likelihood of surgical remission. Residual tumor is managed medically. Irradiation is indicated for patients who cannot tolerate bromocriptine or have tumor progression despite treatment. For macroadenomas of a size or invasiveness precluding surgical remission, an initial trial of bromocriptine is appropriate.38 The management of microadenomas is more controversial. At UCSF, our indications for operative removal are13,14 a desire for pregnancy, the presence of primary amenorrhea, male sex, and the patient’s personal choice. For other patients, bromocriptine is prescribed, and the tumor is monitored at regular intervals with basal PRL measurements and periodic MR images; these tumors rarely expand without a concomitant rise in PRL levels. In patients electing non-operative management initially, two subsequent developments mandate surgery: a progressive elevation in PRL levels approaching 200 ng/mL in an untreated patient or a progressive elevation in PRL levels in a patient taking bromocriptine and enlargement of the tumor as determined by serial MR images.


Induced pregnancy in a patient who has a prolactinoma carries a small but serious risk of complications related to rapid expansion of the tumor.34,39,40 Prophylactic pituitary irradiation has been used in patients who desire pregnancy. If a tumor becomes symptomatic during pregnancy, bromocriptine can be given. We advise against pregnancy for patients known to have a prolactinoma and recommend that bromocriptine therapy be accompanied with contraception by mechanical means. As the risk of a serious complication during pregnancy seems significantly larger than the risk of transsphenoidal surgery, we advise surgical treatment when pregnancy is desired.

Growth Hormone-Secreting Pituitary Adenomas

Clinical Presentation

GH-secreting pituitary adenomas produce acromegaly and gigantism with their classic presentation marked by progressive enlargement of the hands, feet, and coarsening of facial features. Although they progress slowly, these adenomas cause crippling cosmetic and orthopedic deformities and life-threatening metabolic effects, with 50% of untreated patients dead by the age of 50 years41 and a mortality rate 2.4- to 4.8-fold higher than that of the general population.42,43


With considerable accuracy, the diagnosis of acromegaly and gigantism can be made by history and physical examination. Evaluations of GH dynamics, including tests of glucose suppression, thyrotropin-releasing hormone stimulation, and/or insulin intolerance, may be performed. Patients with GH levels greater than 10 ng/mL have active disease,44 and a fasting GH level in serum of less than 5 ng/mL has been considered the benchmark normal value,45–49 although controversy exists regarding the exact definition of remission by GH level,50,51 as well as the optimal assay to use in making the diagnosis.51,52 MR imaging is used to define the anatomic extent of the tumor.


Although various surgical approaches have been used in the past, the treatment of choice is selective transsphenoidal removal of the adenoma. The somatostatin analogues, to date, have not provided a long-term alternative to operation.53,54 Irradiation, used in the treatment of acromegaly since 1909,55 still provides an alternative to surgery, although its efficacy is compromised by the delay in its therapeutic effect and its significant failure rate when used primarily.56–59

Despite the significance of clinical improvement as a measure of therapeutic success, the primary factor determining a cure is the restoration of normal GH production. Radioimmunoassays for GH and insulin-like growth factor (IGF-1) for the documentation of disease activity have provided quantitative information from which to assess the relative efficacy of particular forms of therapy. Based on these quantitations, transsphenoidal surgery is at present the preferred therapy in virtually every case of acromegaly. The results of transsphenoidal surgery for acromegaly at UCSF over a period of 18 years51 have been excellent, with follow-up for 254 patients showing initial postoperative GH levels of less than 5 ng/ml in 76%, and all but 7% of patients remaining in clinical and biochemical remission at long-term follow-up (median = 8 years). The complication rate (i.e., new anterior pituitary hypofunction in 2%, permanent diabetes insipidus in 2%, CSF leak in 4%, and postoperative meningitis in 2%) is low, with no deaths in the series. Because the transsphenoidal procedure is short and postoperative stress minimal, the patient’s age or medical status is rarely a contraindication for surgery.13 The surgical strategy is tailored to the size, shape, location, and consistency of the individual tumor.58 Factors predictive of a poor prognosis are a high preoperative GH level, a larger tumor, and extrasellar extension of the tumor.50,51 Mortality rates among acromegalic patients in clinical remission following transsphenoidal surgery decrease to those of the normal population once GH levels drop below 5 ng/mL, arguing for the prompt institution of effective therapy.51 In primarily nonsurgical series, the value at which mortality rates reset to those of the general population is a GH level of < 2.5 ng/mL.50 For incompletely removed tumors, postoperative irradiation has a high probability (approaching 95%) of preventing future growth, but the risk of radiation-induced hypopituitarism is very high, and there is a rare, but unequivocal, possibility of catastrophic complications.20

Mixed Adenomas

The most common mixed adenoma we encounter at UCSF contains PRL- and GH-secreting cell populations. Women with acromegaly characteristically have amenorrhea and galactorrhea, whereas the men with acromegaly have either no expression of hyperprolactinemia or gynecomastia or in rare cases, gynecomastia and galactorrhea. In a few women with otherwise typical amenorrhea and galactorrhea, and no features of acromegaly, modest elevations of GH were detected unexpectedly. Transsphenoidal adenomectomy is the preferred treatment for patients with mixed adenomas.

Adrenocorticotropic Hormone-Secreting Adenomas

Hypersecretion of ACTH by a pituitary adenoma causes Cushing’s disease and Nelson’s syndrome. Cushing’s disease is the subset of Cushing’s syndrome caused by excessive ACTH secretion by a pituitary adenoma that produces bilateral adrenal hyperplasia and hypercortisolism. Nelson’s syndrome is the result of ACTH hypersecretion by a pituitary adenoma that occurs in certain patients with Cushing’s syndrome following adrenalectomy. The mechanism of Nelson’s syndrome is thought to be an absence of the negative feedback effect of cortisol on the hypothalamus, which leads to chronic overstimulation of the pituitary gland by corticotropin-releasing factor.60

Cushing’s Disease

Cushing’s disease is a serious endocrinopathy that occurs predominantly in women and has its peak incidence during the third and fourth decades of life.

Clinical Presentation

The classic features of Cushing’s disease are centripetal obesity, moon facies, buffalo hump, purple abdominal striae, ecchymoses, acne, and hirsutism. Diabetes mellitus, hypertension, and osteoporosis are features that can cause significant morbidity. Weakness in the form of a proximal myopathy is often one of the most prominent findings. Mental disturbance in a patient with Cushing’s disease should not be underestimated because, to the patient and family, it may be the most distressing feature of the disease.60


The diagnosis of Cushing’s disease and subsequent therapeutic decision making are based on endocrinologic criteria. After verification of sustained hypercortisolism with loss of diurnal variation through the measurement of 17-OH corticosteroids and free cortisol in urine, the diagnosis is established by demonstrating non-suppressibility of steroids by low-dose (1 mg) dexamethasone, less than 50% suppressibility with high-dose (8 mg) dexamethasone, and normal or slightly elevated plasma ACTH levels. Low or undetectable ACTH levels suggest Cushing’s syndrome caused by an adrenal neoplasm, whereas extremely high ACTH levels suggest that the cause is an ectopic ACTH-producing tumor.60 However, in the setting of mild hypercortisolism, some advocate the use of low-dose dexamethasone suppression in conjunction with corticotropin-releasing hormone stimulation to increase the sensitivity of testing.61

Neuroimaging studies only provide anatomic localization after the diagnosis of Cushing’s disease is established. MR imaging is the preferred neuroimaging test for localization,17 although it has a significant incidence of false-negative and false-positive results. If a high-quality MR image does not document an adenoma unequivocally in the setting of a biochemical and clinical diagnosis, bilateral simultaneous selective venous sampling of ACTH from the cavernous sinuses is performed to identify a diagnostic 2:1 ACTH gradient from cavernous sinus to peripheral venous blood.62


The decision to operate relies solely on the clinical and endocrinologic data. Transsphenoidal surgery is the initial treatment of choice.14,60,63 Selective adenomectomy is a successful and safe treatment for Cushing’s disease. The presence or absence of extrasellar extension of the adenoma is the principal determinant of the prognosis.57 During the early postoperative period, a low-dose dexamethasone suppression test confirms a probable surgical remission. Postoperative hypoadrenalism and prolonged suppression of the pituitary-adrenal axis are noted routinely among patients who experience remission of disease after surgery. All patients are maintained on replacement hydrocortisone as long as evidence of hypoadrenalism persists.

Results in our series treated at UCSF60,64 resemble others65–68 in terms of the patient population and its overall results. Remission of disease was achieved in 76% of our 216 patients and the percentage of remission was significantly higher (p < .001) among patients with microadenomas than in those with macroadenomas, and also higher (p < .001) among patients with intrasellar adenomas than among those with extrasellar extension of their adenoma or perforation of the sellar floor by adenoma. Five of six patients in whom no grossly abnormal tissue was found during the exploration were nonetheless cured by surgery. Two patients had diffuse pituitary hyperplasia. Operative mortality and morbidity were minimal. Complications occurred in 9.3% of patients, including persistent diabetes insipidus in 2.8% of patients, and visual deficits, CSF leak, and persistent sinusitis in fewer than 2% each. Adults and children do not differ in their response to transsphenoidal microsurgery,14 and transsphenoidal adenomectomy is as effective therapeutically in children as in adults. Our results, like those in other large series, 66,69 refute the notion that diffuse pituitary hyperplasia might constitute up to 25% of the cases of Cushing’s disease.70,71

Pituitary irradiation can be used as primary or adjuvant therapy for Cushing’s disease. Heavy-particle irradiation has a high cure rate and usually can be given as a single treatment with multiple ports, but is available at only two centers in the United States and has a higher rate of complications than conventional irradiation. Because of high cure rates reported with conventional irradiation for children with Cushing’s disease, some institutions use pituitary irradiation as the standard therapy for children. However, the lag period between treatment and remission is typically several months. In adults, pituitary irradiation has been much less effective.

Pharmacologic therapy can afford palliation for patients with Cushing’s disease or Nelson’s syndrome who have tumors that are resistant to surgery and radiation therapy. Various drugs60 are used in order to reduce the secretion of ACTH by the pituitary or to block steroidogenesis by the adrenal glands. Pharmacologic agents that inhibit secretion of ACTH and corticotropin-releasing hormone include cyproheptadine and bromocriptine; drugs that inhibit cortisol synthesis include aminoglutethimide, metyrapone, ketoconazole, and mitotane; and those that block the action of cortisol at the glucocorticoid receptor level include RU 486.72 Except for mitotane, whose use is limited by its toxicity, the action of these drugs ceases almost immediately with discontinuation of treatment.72 They can be used as a temporary measure to improve a patient’s condition in preparation for surgery or concurrently with pituitary irradiation, or after both surgery and irradiation have failed to produce remission.


Selective adenomectomy is a successful and safe treatment for Cushing’s disease and is preferable to bilateral adrenalectomy, pituitary irradiation, or total hypophysectomy as the primary treatment.60 It provides a likely selective removal of the ACTH-secreting adenoma, immediate cure of the hypercortisolism, preservation of pituitary function, and minimal morbidity. The overall percentage of remissions compares favorably with the approximately 80% obtained with primary total hypophysectomy, and adenomectomy does not result in the inevitable hypopituitarism accompanying hypophysectomy.73 Because bilateral adrenalectomy is associated with a greater perioperative mortality (up to 5%), with an occasional persistence of hypercortisolism due to incomplete adrenalectomy, and frequently (20–40%) with the development of Nelson’s syndrome, it should be used only as a last resort after pituitary surgery, irradiation, and pharmacologic therapy have all failed.66

Although primary irradiation of the pituitary gland can eventually produce remission in 50 to 80% of patients with Cushing’s disease, hypercortisolism may not resolve for many months after pituitary irradiation.74–76 In contrast, selective adenomectomy corrects the condition immediately.66,76 We recommend transsphenoidal pituitary exploration as the treatment of first choice for most patients with Cushing’s disease, reserving radiation therapy for patients who are either at extremely high surgical risk or harbor residual adenoma after transsphenoidal surgery. In consenting adults, if no adenoma is observed during surgical exploration, then total hypophysectomy can be performed because the result is usually a cure. For children in whom exploration shows no evidence of an adenoma, postoperative irradiation, drug therapy, or adrenalectomy is recommended.60


Because patients can develop recurrent Cushing’s disease as late as 8 years after surgery, patients in clinical remission should undergo periodic endocrinologic re-evaluations. The anatomic reasons for the failure of initial operations include extrasellar extension and invasion of the cavernous sinus. Re-operation is a safe and effective treatment for many recurrent tumors, with the advent of image-guided surgical technology further minimizing risks.77 The majority of patients undergoing re-operation for recurrent Cushing’s disease derive benefit and many are cured,60 sometimes with the addition of chemotherapy. Medical management of recurrent tumors is effective in the long term only in patients with prolactinomas who tolerate, and whose tumors are sensitive to, bromocriptine.

Nelson’s Syndrome

Nelson’s syndrome occurs in 20 to 40% of patients who undergo bilateral adrenalectomy, once the primary treatment for Cushing’s disease despite its significant drawbacks. The tumors causing Nelson’s syndrome are much more likely to be large and invasive than are those causing Cushing’s disease, and although in many patients the tumor is indolent, in a significant minority it is aggressive or frankly malignant and directly causes death.14 The intervals between adrenalectomy and transsphenoidal surgery for Nelson’s syndrome range from a few months to more than 2 decades, reflecting the unpredictable behavior of these tumors.

Clinical Presentation

Because of the large size and invasive nature of tumors causing Nelson’s syndrome, headaches and visual disturbances are more common than in association with Cushing’s disease. The documentation of extremely high plasma ACTH levels, often several thousand picograms per milliliter, is sufficient to make the diagnosis, which can be corroborated by MR imaging of the sella. Hyperpigmentation is the hallmark of Nelson’s syndrome.14


The diagnosis of Nelson’s syndrome is straightforward. The loss of cortisol inhibition caused by adrenalectomy allows the pituitary gland to secrete very large amounts of ACTH and may promote rapid growth of the adenoma. Cutaneous melanocytes are stimulated by the high levels of ACTH to produce the characteristic hyperpigmentation of Nelson’s syndrome. The development of hyperpigmentation in a patient known to have undergone adrenalectomy for Cushing’s syndrome is diagnostic of Nelson’s syndrome.14


In cases of Nelson’s syndrome, the prognosis is guarded and generally unfavorable,63 but transsphenoidal surgery offers the best hope of controlling the disease. Craniotomy should be used only for patients in whom there is large parasellar or suprasellar extension or an unusually small sella turcica that precludes adequate access by the transsphenoidal approach. Radiation and drug therapy are important adjuvants because most patients who develop the syndrome usually have large and invasive tumors with extrasellar extension by the time they present for treatment, and complete removal of the tumor is possible in fewer than 30%. Heavy particle radiation is more effective than conventional radiation, but the former is suitable only for adenomas confined to the sella. Fortunately, there has been a profound reduction in the incidence of Nelson’s syndrome as transsphenoidal microsurgery has replaced bilateral adrenalectomy as the primary treatment for Cushing’s disease.14

Endocrine-Inactive Pituitary Neoplasms

Etiology and Epidemiology

Endocrine-inactive adenomas, less precisely termed nonfunctioning or nonsecreting pituitary adenomas, constitute about 25% of all clinically apparent pituitary neoplasms.78 Although these adenomas are generally associated with the older population (mean age in both sexes, 52 years),79 at least one study suggests that their prevalence among younger men and women may be underestimated.80


Endocrine-inactive adenomas were formerly classified as chromophobic adenomas, but this term is not useful because the agranular appearance of the tumors under the light microscope is misleading. Ultrastructural studies have disclosed secretory granules in “chromophobic” adenomas, and sensitive radioimmunoassays show that as many as 50% of them produce a hormone.12,81 The pituitary glycoprotein hormone alpha-subunit has been demonstrated in many endocrine-inactive, undifferentiated pituitary adenomas.80,82,83 It now appears likely that endocrine-inactive pituitary adenomas that are not clinically evident nevertheless release small quantities of hormones, primarily gonadotropins, possibly from only a small percentage of the tumor cells.84 Excessive secretion of gonadotropins and/or their subunits by these adenomas is rare and may occur primarily in men. Women, however, may show an elevated ratio of alpha-subunit to luteinizing hormone and follicle-stimulating hormone, which may be useful in making the diagnosis.85 The null cell adenoma, characterized by Kovacs et al., appears now to be the only truly nonsecreting tumor, but it too may have an as yet unidentified secretory product.4

Clinical Presentation

Endocrine-inactive adenomas have an insidious clinical progression, and by the time patients present for a diagnosis, the tumor is usually a macroadenoma producing symptoms caused by mass effect or hypopituitarism.78 The most frequent symptoms are headache and visual disturbances caused by encroachment of the adenoma on the visual pathway.79


Both thin-section MR imaging and high-resolution computed tomography detect the macroadenomas accurately, but MR imaging is the superior technique because of the greater soft-tissue contrast it provides, permitting clearer visualization of the adjacent optic chiasm, optic nerves, cavernous sinuses, and carotid arteries.17 Visual evoked potential evaluations reliably assess the function of the intracranial visual pathways and can be more sensitive than conventional methods of examination.86

Patients suspected of having an endocrine-inactive adenoma should undergo MR imaging, assessment of pituitary hormone function, and a determination of the pituitary glycoprotein hormone alpha-subunit in serum.78 Elevated or high-normal gonadotropin levels suggest an underlying gonadotropic adenoma, although pituitary adenomas secreting gonadotropins are often diagnosed as endocrine-inactive adenomas because of the clinical findings associated with mass effect, and the absence of findings associated with acromegaly or Cushing’s disease.87 Some patients have tumors producing no hormone or tumors with defective hormone biosynthesis that obscures detection of hormone hypersecretion. In a few patients, the endocrine-inactive pituitary adenoma interferes with the pituitary stalk and produces moderate hyperprolactinemia (50–100 ng/mL) as a result of “stalk section effect.”


An endocrine-inactive tumor in an asymptomatic patient with unimpaired pituitary function should, with some exceptions, be left alone and its course followed with serial MR images.14 For patients with symptomatic endocrine-inactive adenomas, transsphenoidal microsurgery is the preferred treatment. In some patients, transsphenoidal surgery improves pituitary function,14,19,78,88 but even in patients with very large or giant adenomas, the transsphenoidal approach permits rapid decompression of the optic nerves and chiasm, averts significant pituitary insufficiency in the majority of cases,89 is well tolerated by elderly patients,90 and is associated with low morbidity, mortality,89 and recurrence rates.

Conventional radiation therapy is often recommended when there is evidence of residual tumor postoperatively and/or significant extrasellar extension preoperatively.78 However, an increasing proportion of endocrine-inactive tumors is being followed rather than referred for radiation immediately after surgery because of the potential for cure following a gross total resection.

Medical treatment of endocrine-inactive adenomas with bromocriptine, whether preoperatively or as primary therapy, is controversial. There are isolated cases in which bromocriptine is tolerated well and produces impressive results.87,91 The consensus remains, however, that with the possible exception of pituitary adenomas demonstrating recent growth, bromocriptine is unlikely to cause growth arrest or to reduce the size of endocrine-inactive pituitary adenomas.92,93

Figure 82.3. Algorithm for the evaluation of patients suspected of harboring a pituitary adenoma.

Figure 82.3

Algorithm for the evaluation of patients suspected of harboring a pituitary adenoma.


Wilson CB. Surgical management of endocrine-active pituitary adenomas. In Oncology of the Nervous System. In: Walker MD, editor. Occology of the nervous system. (Series volume. In: McGuire WL, editor. Cancer treatment and research.) Bostson: Martinus Nijoff Publishers; 1983. p. 117–150.
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