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CHAPTER 24 PITUITARY TUMORS: OVERVIEW OF THERAPEUTIC OPTIONS

CHAPTER 24 PITUITARY TUMORS: OVERVIEW OF THERAPEUTIC OPTIONS
Principles and Practice of Endocrinology and Metabolism

CHAPTER 24 PITUITARY TUMORS: OVERVIEW OF THERAPEUTIC OPTIONS

PHILIPPE CHANSON

Clinical Classification
General Therapeutic Principles of Surgery and Irradiation

Surgery

Irradiation Therapy
Therapeutic Options and Results by Type of Pituitary Adenoma

Growth Hormone–Secreting Pituitary Adenomas

Prolactin-Secreting Tumors

Adrenocorticotropic Hormone–Secreting Adenomas

Thyroid-Stimulating Hormone–Secreting Adenomas

Clinically Nonfunctioning Pituitary Adenomas
Prognosis of Pituitary Adenomas and Therapeutic Perspectives

Prognosis

Conclusions and Perspectives Concerning Treatment of Pituitary Adenomas
Chapter References

Chapter 21, Chapter 22 and Chapter 23 discuss, respectively, medical, radiologic, and surgical therapies of pituitary tumors. This chapter reviews the current literature and draws on the author’s own experience to systematically discuss and compare the different therapeutic options, their applicabilities, and their limitations. Whenever possible, an attempt has been made to categorize, in a statistical manner, response rates and recurrences.
Pituitary tumors are relatively common neoplasms of the adenohypophyseal cells; they represent ~15% of all intracranial tumors.1,2 The prevalence of clinically recognizable pituitary adenomas is ~200 cases per million, and new cases number 15 per million per year.3 However, asymptomatic adenomas (mostly microadenomas) are found in 6% to 20% (mean, 11%) of presumably normal pituitary glands. This has been demonstrated by autopsy studies4,5 and by systematic magnetic resonance imaging (MRI) studies.6 Thus, pituitary adenomas—whether detected by clinical manifestations or by pituitary imaging that is performed for unrelated reasons (i.e., incidentalomas)—are becoming more frequently diagnosed. Therapeutic recommendations are based on previously reported studies that have evaluated results of various treatment strategies. However, few large comparative trials have been undertaken. Thus, therapeutic guidelines often are somewhat subjective.
An accurate classification of pituitary adenomas depends on immunocytochemical studies that are performed on tumoral tissue removed at surgery.2 However, not all pituitary tumors require surgery. Thus, for practicality, and for simplification of therapeutic decisions, a clinical classification is used, which is based on the presence or absence of a hypersecretion syndrome. Generally, the clinical classification and the histopathologic classification concur (Fig. 24-1).

FIGURE 24-1. Distribution of the various types of pituitary adenomas in a surgical series. (TSH, thyroid-stimulating hormone; GH, growth hormone; ACTH, adrenocorticotropic hormone.) (From P. Derome, Hôpital Foch, Suresnes, France.)

CLINICAL CLASSIFICATION

1.
Growth hormone (GH)-secreting adenomas are responsible for acromegaly. On immunocytochemical analysis, these adenomas may be purely GH-secreting or mixed (secreting GH and prolactin [PRL] or GH and a subunit).

2.
PRL-secreting adenomas are responsible for hyperprolactinemia. Immunocytochemically, they can be composed of pure PRL-secreting adenomatous cells or can be mixed (secreting PRL and GH, or PRL and a subunit).

3.
Corticotropin-secreting adenomas are associated with Cushing syndrome (when Cushing syndrome is due to a pituitary microadenoma, the condition is termed “Cushing disease”). On immunocytochemical analysis, these ade nomatous cells stain for adrenocorticotropic hormone (ACTH), either alone or in association with other peptides.

4.
Thyrotropin (thyroid-stimulating hormone, or TSH)–secreting pituitary adenomas are responsible for thyrotoxicosis, which occurs in conjunction with an inappropriate secretion of TSH. The TSH immunostaining may be isolated or may be associated with a subunit, GH, or PRL.

5.
Clinically nonfunctioning pituitary adenoma (NFPA) is the preferred term for designating a pituitary adenoma that is not hormonally active (i.e., not associated with one of the above clinical syndromes); patients with NFPAs do not have acromegaly, a hyperprolactinemic syndrome, Cushing syndrome, or hyperthyroidism. Usually, the tumor has been found because of a tumor-mass effect or has been an incidental discovery. The term “clinically NFPA” is preferred to “chromophobe” adenoma (the latter term was used before the routine use of immunocytochemical staining); it also is preferable to the term “nonsecreting adenoma,” because immunocytochemical analysis has demonstrated that the majority of these lesions are, indeed, able to secrete one or more of the pituitary hormones. However, they may not be associated with increased plasma levels of the hormone (silent adenoma), or they may be associated with increased levels of a hormone that often does not produce a recognizable clinical hypersecretion syndrome (e.g., FSH, LH, or free a subunit). Whatever an immunocytochemical study of such surgically removed NFPA may reveal, the therapeutic management is the same.
The classification above is used in this chapter.
GENERAL THERAPEUTIC PRINCIPLES OF SURGERY AND IRRADIATION
The management of pituitary tumors commences with a careful definition of the location and extent of the lesion and the endocrinologic abnormalities. The principles of therapy are based primarily on these factors and their clinical sequelae. Any direct effect of the mass (e.g., vision impairment) must be addressed, and any endocrinologic dysfunction must be corrected. Certain hormonal deficiencies, particularly those of cortisol or thyroid hormone, should be corrected immediately. Possible complications of therapy, most prominently hypopituitarism or tumor recurrence, can occur many years (up to 30 years) after therapy and must be carefully considered.
The choice of treatment modality is determined by several factors: (a) the need for immediate relief of a mass effect, (b) the need to relieve an endocrine abnormality, (c) the potential for obtaining long-term control, and (d) the character and frequency of possible associated morbidity.
Surgery and radiotherapy are the two main available tools for radical treatment of all types of pituitary adenomas. Their common technical characteristics and side effects are presented in this section. More specific medical modalities, applicable to certain types of pituitary tumors, are detailed in the later section, which deals with therapeutic options according to the type of pituitary adenoma.
SURGERY
The purpose of surgery in the management of pituitary adenomas includes, according to the circumstances, the histologic confirmation of the diagnosis; the correction of tumor-mass effect; the complete excision of a microadenoma and, if possible, of a macroadenoma; and the reduction of the tumor bulk of an invasive adenoma. Whatever the immunocytochemical type, the greater the extent to which an adenoma is small, is enclosed, and is noninvasive, the better are the results of surgical removal. In most cases, either a transsphenoidal or a subfrontal transcranial approach is used7,8 and 9 (see Chap. 23).
TRANSSPHENOIDAL TECHNIQUE
The transsphenoidal approach, via a sublabial incision, is now preferred by most pituitary neurosurgeons for the vast majority (>95%) of patients with pituitary tumors. This technique allows entry into the facial portion of the sphenoid sinus, through which access is gained to the pituitary fossa. Binocular surgical microscopy is coupled with fluoroscopic monitoring to obtain direct visualization of the surgical field. The transsphenoidal approach offers the capability of tumor destruction by resec tion, by coagulation, or by freezing. This technique is indicated for removal of a tumor that is confined to the sella turcica, removal of a tumor associated with cerebrospinal fluid (CSF) rhinorrhea or of a pituitary apoplexy, removal of a tumor with sphenoidal extension, removal of a tumor with only modest suprasellar extension, or removal of a tumor which has fluid characteristics that allow the suprasellar part of the adenoma to flow down by gravity into the sellar cavity.
Contraindications to use of the transsphenoidal approach include the presence of dumbbell-shaped tumors with constriction at the diaphragma sellae, massive suprasellar tumors, lateral suprasellar extension of a tumor, and an incompletely pneumatized sphenoid bone. Morbidities include transient diabetes insipidus and, rarely, meningitis or persistent CSF rhinorrhea (Table 24-1). When a selective resection of an adenoma is possible, subsequent hypopituitarism is uncommon.

TABLE 24-1. Mortality and Morbidity of Transsphenoidal Surgery

SUBFRONTAL APPROACH
The subfrontal approach, via craniotomy, is limited to surgery for dumbbell-shaped lesions for which removal by a transsphenoidal approach is impossible; for tumors with suprasellar extension involving the chiasm; or for tumors involving the surrounding vascular structures. The disadvantages of the subfrontal approach include a high morbidity (increased duration of hospitalization, seizures, memory loss), and increased mortality resulting from damage to vital structures. Furthermore, a substantial incidence of postoperative hypopituitarism and diabetes insipidus is seen.
COMBINED TRANSSPHENOIDAL AND SUBFRONTAL APPROACHES
When combined transsphenoidal and subfrontal approaches are used, due to the lower risk of side effects and complications with the transsphenoidal operation as compared with the subfrontal approach, transsphenoidal surgery may be used as the primary surgery, and the removal of a tumor remnant may be performed, when necessary, by a subsequent subfrontal route.
IRRADIATION THERAPY10,11,12,13,14,15,16,17,18,19,20,21 and 22
Before the advent of transsphenoidal surgery, radiation therapy was extensively proposed as the primary treatment for pituitary adenomas. In general, such irradiation is external mega-voltage photon therapy, although proton beams, cobalt-knife radiosurgery, and linear accelerator focal stereotactic technology are all potentially applicable to pituitary adenomas.21,23,24 (The implantation of pellets containing radioactive isotopes [e.g., yttrium-90, gold-198] has been completely abandoned.)
The treatment techniques are variable. The dosage is tailored to the tumor volume, with a minimum dose being delivered to adjacent structures. Optimal techniques for conventional external radiotherapy include use of bilateral coaxial wedge fields plus a vertex field, moving arc fields, and 360° rotational fields12,21,25 (see Chap. 22). Although the use of two bilateral opposed fields is occasionally necessary for large, asymmetric tumors, it is to be discouraged because of the large dose that is delivered to the temporal lobes. Modern radiotherapy simulator facilities together with current generation computed tomography (CT) or MRI scanning allow the fields to be accurately molded around the tumor volume (conformational irradiation). The day-to-day reproducibility of the field setup should be within 2.0 mm. Optimum doses are based on evidence that doses <40 Gy provide a lower probability of tumor control; doses >50 Gy or fractions >2 Gy per day are associated with higher complication rates, including injury to the optic nerves or chiasm, and hypopituitarism. Thus, a dose of 50±5 Gy is advisable. If the bulk of the tumor is completely removed surgically, leaving only a minimum residue, and if the patient is young, 45 to 50 Gy is advisable. However, if a large residual lesion is present after surgical resection, if recurrent tumor is found, or if significant suprasellar extension is present, a higher dose (50 to 55 Gy depending on tumor bulk) is recommended.12,21,25 As is the case with surgery, radiotherapy must be performed by skilled radiotherapists who have accumulated considerable experience in pituitary irradiation.
The major problem after pituitary irradiation (particularly when used as an adjunct to surgery) is the development of partial hypopituitarism or panhypopituitarism. Panhypopituitarism develops in approximately half of patients.13 The variably quoted figures are 30% to 45% for ACTH deficiency, 40% to 50% for gonadotropin deficiency, and 5% to 20% for TSH deficiency.12,13 and 14 The prevalence of deficiencies increases with the duration of follow-up: 100% of patients are GH deficient, 96% are gonadotropin deficient, 84% are ACTH deficient, and 49% are TSH deficient after a mean follow-up of 8 years.16 Hypothalamic-pituitary dysfunction may take up to 20 years to develop.20 The sensitivity of the hypothalamus and pituitary to the effects of radiation is well illustrated by the very frequent occurrence of endocrine dysfunction that is observed in patients irradiated for nasopharyngeal, extracranial, or primary brain tumors, even though these lesions were anatomically distinct from the hypothalamic-pituitary region.19 Accordingly, prolonged and repeated assessment of pituitary function is mandatory after irradiation therapy. This should permit a precise detection of pituitary deficiencies and the selection of appropriate replacement therapy. Nevertheless, one should emphasize that hormonal side effects of irradiation therapy, if diagnosed early, are easily managed.
Other disadvantages of radiotherapy include a delayed therapeutic benefit for patients who have hormonally active tumors, irradiation-induced optic neuropathy, cortical injury, and, rarely, irradiation-induced malignancies (e.g., meningioma, astrocytoma).15,26
The term “radiosurgery” is applied to high-precision localized irradiation, given in one session. The “gamma knife” is one of these techniques and uses cobalt sources arranged in a hemisphere and focused onto a central target. High-precision stereotactic radiosurgery may also be delivered by adjusted linear accelerators. The aim of radiosurgery is to deliver a high dose of irradiation that is more localized than would be achieved with conventional radiotherapy. However, this is possible only for relatively small adenomas (<3–4 cm in diameter) and when the margins of the tumor are distant by >5 mm from the optic chiasm or optic nerves (due to the risk of irradiation-induced optic neuropathy that causes visual impairment). The long-term results of radiosurgery on hypersecretion, as on subsequent tumor growth, are presently unknown27 (also see Chap. 22).
THERAPEUTIC OPTIONS AND RESULTS BY TYPE OF PITUITARY ADENOMA
The recommendations for treatment of the different types of adenomas are summarized in Table 24-2.

TABLE 24-2. Multidisciplinary Treatment Decisions Based on Tumor Type in Pituitary Adenomas

GROWTH HORMONE–SECRETING PITUITARY ADENOMAS
THERAPEUTIC OPTIONS
Surgery and Radiotherapy. Surgery and radiotherapy, as previously summarized, are commonly used in the treatment of acromegaly.
Medical Treatment. Bromocriptine and other dopamine agonists are able to improve symptoms of acromegaly in a few patients and to decrease GH secretion.28,29
Somatostatin, the hypothalamic GH-release inhibitory factor and its analogs, SMS 201-995 (octreotide) and BIM 23014 (lan-reotide), are able to reduce GH secretion. The native somatostatin peptide has a half-life that is too short for it to be administered easily. However, octreotide, given subcutaneously three times daily, has been shown to control GH hypersecretion and to decrease tumor volume in a significant proportion of patients with acromegaly with relatively few side effects.30,31,32,33,34,35 and 36 The availability of a long-acting form of octreotide allows once-monthly intramuscular injections with the same efficacy.37 Another somatostatin analog, lanreotide, when encapsulated in microspheres, has a prolonged release; it has proved to be effective in lowering levels of GH and insulin-like growth factor-I (IGF-I), and often in decreasing the tumor mass of acromegalic patients, in a manner comparable to that of octreotide.38,39,40 and 41 The side effects of somatostatin analogs are benign. Digestive problems (i.e., abdominal cramps, diarrhea, flatulence) are minor and most often transitory. Cholelithiasis occurs in 10% to 55% of patients, with the incidence related to the duration of the study.30,33,34,36 Generally, it is asymptomatic and is treated conservatively. Despite the reduction in insulin secretion due to the use of somatostatin analogs, glucose-tolerance alterations are of minor significance. Somatostatin analogs are very expensive drugs and need to be given for the remainder of life.
Importantly, scintigraphy after administration of labeled octreotide (somatostatin-receptor scintigraphy) allows for the visualization of pituitary tumors.42 The resulting images are thought to reflect the concentration of the somatostatin receptors that are present at the surface of the tumor cells. However, scintigraphic findings are poor predictors of long-term results of treatment with somatostatin analog, regardless of the type of pituitary adenoma43 (also see Chap. 169).
CRITERIA OF CURE OF ACROMEGALY
The results of the various modes of therapy for acromegaly should be analyzed according to stringent criteria. Currently, “cure” (or good control) of acromegaly is defined by plasma GH levels: the mean of sequential sampling or the nadir after oral glucose administration should be <2.5 µg/L and the IGF-I level should be normal.44,45 Indeed, when these goals are achieved, the life expectancy of patients with acromegaly seems comparable to that of the general population.46,47,48,49,50 and 51 In the future, even more stringent criteria (nadir GH after oral glucose administration of <1 µg/L, and age- and sex-normalized IGF-I levels without clinical indications of activity) will probably be proposed for defining good therapeutic control of acromegaly.52 In the interim, the following section, using the currently accepted criteria for good control (plasma GH of <2.5 µg/L and normal IGF-I level), compares the effects of the different treatments as indicated by several studies.
RESULTS OF TREATMENT
Transsphenoidal Surgery. According to the stringent criteria indicated above, 42% to 62% of patients can be considered to have their disease “well controlled” by surgery alone.8,45,48,50,53,54,55,56,57 and 58 (Table 24-3). The results depend on the size of the tumor: surgery is able to cure 61% to 91% of patients with microadenomas and 26% to 60% of those with macroadenomas. When the macroadenoma is very large, or when parasellar or sphenoid sinus invasion has occurred, the cure rate decreases to 17% and 40%, respectively.8 Also, the success rate of surgery in patients with acromegaly varies according to preoperative GH levels: surgical treatment is successful in ~70% of patients with preoperative GH levels of <10 µg/L, 43% to 55% of those with GH levels of 10 to 50 µg/L, and 18% to 40% of those with GH levels of >50 µg/L.8,54 The relapse rate after surgical cure is <3%53,54,59,60 (also see Chap. 12 and Chap. 23).

TABLE 24-3. Results of Transsphenoidal Surgery for Treatment of Acromegaly with Stringent Criteria of Cure

Irradiation Therapy. Irradiation therapy is able to decrease GH levels in a large proportion of patients. Mean plasma GH levels of <5 µg/L are obtained in ~50% of patients (40% to 80%, depending on the length of follow-up).18,22,61,62,63,64,65 and 66 However, when more stringent criteria for cure (as stated earlier) are applied, radiation therapy leads to cure of the disease in only 5% to 38% of the cases after a median follow-up of ~7 years22,65,66 (Table 24-4). Irradiation is almost always followed by hypopituitarism, however, and the full impact on GH hypersecretion is delayed for many years. Preliminary results with radiosurgery are now available, but the follow-up is short. In one study,67 at 20 months, 20% of patients had “normalized” GH and IGF-I levels after radiosurgery, and the mean delay for “normalization” of hormonal parameters was reduced (1.4 years as opposed to 7.1 years after conventional radiotherapy).68 Studies involving a higher number of patients followed for a longer period of time and assessed with more stringent criteria of cure are needed before one can conclude that radiosurgery is superior to conventional radiotherapy.

TABLE 24-4. Success Rate of Radiation Therapy for Acromegaly with Different Criteria of Cure

Therapy with Bromocriptine and Other Dopaminergic Agonists. Treatment with bromocriptine or other dopaminergic agonists produces improvement in clinical symptoms of acromegaly in half of the patients. These drugs substantially decrease GH levels in some patients but only rarely normalize GH and IGF-I levels (i.e., in <10% of cases).28 Better results seem to be obtained with cabergoline than with bromocriptine, however; in a multicenter study, nearly 40% of patients acromegaly treated with cabergoline were reported to have normalized IGF-I levels.29
Therapy with Somatostatin Analogs. Somatostatin-analog therapy has now gained wide acceptance in the medical treatment of acromegaly. GH levels are decreased in 50% to 80% of patients treated with octreotide subcutaneously three times daily.30,33,34,35 and 36,45,69,70 With this treatment, up to 50% of acromegalic patients may be considered as “cured” (GH plasma levels of <2 µg/L [20–30% of cases] and/or normal IGF-I [20–60% of cases]) (Table 24-5). Similar results are obtained with lanreotide LAR (long-acting release), 30 mg administered intramuscularly every 10 or 14 days (GH plasma levels of <2 µg/L [30–70% of cases] and/or normal IGF-I [40–70% of patients]),38,39,40 and 41 or with octreotide LAR. This latter drug has been administered intramuscularly every month at a dose of 20 to 30 mg (yielding GH plasma levels of <2 µg/L [50–60% of patients] and/or normal IGF-I [60–90% of cases])37,71,72 and 73 (see Table 24-5). Such variations in the data obtained from one study to another is probably explained by differences in the methods used for IGF-I assay and by differences in the inclusion criteria used. Thus, in some of the studies assessing the efficiency of long-acting forms of somatostatin analogs, patients were included if they had previously been shown to be responsive to subcutaneous octreotide, whereas in others, patients were entered blindly, without any knowledge of whether or not they were responsive. As demonstrated by a multicenter prospective study, the efficacy of octreotide as primary treatment (in 26 previously untreated patients) proved to be equivalent to that of secondary treatment (in 81 patients previously treated with surgery and/or radiotherapy).70

TABLE 24-5. Effects of Long-Term Treatment of Acromegaly with the Somatostatin Analogs Octreotide and Lanreotide with Various Modes of Preparation and Administration and Different Criteria of Cure

A small reduction in tumor volume may be observed (in general at the level of the suprasellar expansion) in 15% to 70% of patients with acromegaly30,33,34,35,36 and 37,39,40 and 41,45,69,70,71,72 and 73 (see Table 24-5).
Administration of a combination of a dopamine agonist and a somatostatin analog may be beneficial for some patients, but long-term studies assessing this therapeutic association are not currently available.
GH-receptor antagonist therapy may be effective in the control of the clinical symptoms of acromegaly and normalizes IGF-I levels in a substantial number of patients.
SUMMARY OF RECOMMENDATIONS FOR TREATMENT OF GROWTH HORMONE–SECRETING ADENOMAS
Table 24-2 summarizes the treatment decisions for GH-secreting adenomas.

1.
Transsphenoidal surgery is the first-line therapy, except when a macroadenoma is extremely large or when surgery is contraindicated.

2.
Postoperative radiation therapy (50 to 55 Gy) is performed for partially resected tumors or when GH levels remain elevated after a trial of a somatostatin analog.

3.
Somatostatin analogs are best used when surgery is contraindicated or when the surgery has failed to normalize GH levels. These drugs are also used when waiting for the delayed effects of radiation therapy. Somatostatin analogs may be a reasonable primary therapeutic modality if the possibility of surgical cure is low (as in patients with large and/or invasive tumors), provided that the tumor does not threaten vision or neurologic function.
PROLACTIN-SECRETING TUMORS
THERAPEUTIC OPTIONS
Occasionally, surgery and, more rarely, radiotherapy may be used. Their techniques and side effects have been detailed in the first section (see earlier).
In the vast majority of cases, however, medical therapy with dopamine agonists is chosen. Bromocriptine or other ergot derivatives with dopaminergic properties (e.g., pergolide, quinagolide, cabergoline) are used. Bromocriptine effectively reduces elevated serum PRL levels in most patients with PRL-secreting pituitary adenomas.74,75 and 76 Thus, it is the primary treatment for microadenomas. Furthermore, macroprolactinomas have also been successfully managed medically.74,77,78 and 79 Bromocriptine not only decreases PRL levels but also is able to produce a dramatic reduction in tumor volume. This antitumor effect of bro-mocriptine may be very rapid. In the presence of chiasmal compression by a macroadenoma, visual improvement often occurs within the first hours after the initiation of bromocriptine therapy. Ovulatory and menstrual cycles may resume in 75% to 80% of female patients.74,78 Patients with macroade-nomas who become pregnant are at risk for complications related to tumor growth. For these patients, pregnancy should be delayed by contraceptive methods, while shrinkage is attempted with bromocriptine. Definitive ablative therapy of macroadenomas may be performed before pregnancy.74,78 However, patients with intrasellar microadenomas or macro-adenomas of <12 mm are at <6% risk for any substantial tumor growth or associated complications.80,81 and 82 Bromocriptine should be discontinued when pregnancy is confirmed, although early concerns regarding the teratogenicity of this drug have not, to date, been substantiated.74 Quinagolide and cabergoline are two other dopamine agonists now available in the United States and/or in Europe. Quinagolide is not an ergot derivative; it binds specifically to dopamine type 2 receptors. It is at least as effective as bromocriptine83 and may be useful in rare cases of resistance84,85 and 86 or intolerance86 to bromocriptine. It offers the advantage of once-daily administration. Cabergoline is notable for its very long duration of action (half-life is ~70 hours). This allows a once- or twice-weekly oral administration.87 The efficacy of cabergoline is at least equal to that of bro-mocriptine and tolerance to it is better.87,88 In patients with macroprolactinoma, cabergoline is quite effective in reducing PRL levels and in producing tumor shrinkage.89,90 and 91 Furthermore, cabergoline normalizes serum PRL levels in a significant number of patients who are resistant to bromocriptine and/or quinagolide90 (see Chap. 13).
RESULTS OF TREATMENT
Transsphenoidal Surgery
MICROADENOMA. In a compilation of various studies involving a total of 1224 patients, transsphenoidal resection was found to normalize PRL levels in 71.2% of patients.74 Cure rates vary according to preoperative serum PRL level; when the PRL level is >200 µg/L, the cure rate decreases to 13%. After surgery, up to 88% of women desiring conception conceived within 1 year.74,92 Initially, the recurrence rate after surgical success was thought to be as high as 50%; however, more recent studies report a recurrence rate from 5% to 18% after a 10-year follow-up.74,92,93 Nonetheless, even if hyperprolactinemia should relapse, it tends to remain mild and usually without any clinical consequences. Ten years after surgery, 55% to 73% of patients have normal serum PRL levels, and 75% have normal menstrual cycles.92,93 and 94
MACROADENOMA. The success rate for transsphenoidal surgery is much lower for macroadenomas. According to a compilation of 1256 such patients from reported series, the mean cure rate was 31.8%.74 Moreover, after apparent initial cure, 18% of patients relapsed. Surgical results were proportional to the pre-operative size of the tumor and to the initial level of serum PRL. When the adenoma size was >20 mm and the serum PRL levels were >200 µg/L, the cure rate was <15%.74
Medical Therapy. Dopamine agonists are able to decrease PRL levels in 73% to 95% of patients, whatever the size of their adenomas; moreover, the drugs produce a decrease in tumor volume in 77% of patients with a macroprolactinoma.74,77,79,83,89,91 This tumor shrinkage may be dramatic (>50% of initial volume in half of the patients). Treatment with dopamine agonists is prolonged and often lifelong. Indeed, after withdrawal of treatment, the tumor usually returns to its original size, often within days to weeks, and the serum PRL levels again rise.
In patients who are resistant to bromocriptine, other dopamine agonists such as quinagolide or cabergoline may be a useful alternative; quinagolide allows normalization of PRL levels in 16% to 20% of cases, and cabergoline in 80% of patients.84,85 and 86,90 In cases of intolerance of bromocriptine, PRL may be normalized by quinagolide in more than half of patients.86 Tolerance of cabergoline has proven to be better than tolerance of bromocriptine, so that larger doses can be used in cases of incomplete response.87,88,89,90 and 91
Irradiation Therapy. Irradiation therapy is indicated only in rare cases of surgical failure in which the patient has subsequently been found to be intolerant of or resistant to dopamine agonists 20% to 30%,12,74,95,96 and only half of such patients have normal serum PRL levels 3 to 4 years and 8 years after irradiation therapy, respectively.97
SUMMARY OF RECOMMENDATIONS FOR TREATMENT OF PROLACTIN-SECRETING PITUITARY ADENOMAS
Table 24-2 summarizes the treatment decisions for prolactin-secreting pituitary adenomas.

1.
Selected hyperprolactinemic patients with microade-nomas may be carefully followed without treatment if regular ovulatory cycles occur, or if the patient is post-menopausal.

2.
Patients with microadenomas are usually treated with dopamine agonists. In the uncommon circumstance that transsphenoidal surgery was the initial choice, dopamine agonists may be useful if the serum PRL levels remain elevated postoperatively. When medical therapy with dopamine agonists is the primary treatment, secondary surgery may occasionally be proposed in cases of resistance to or intolerance of these drugs. In dopamine-treated microprolactinoma patients, pregnancy can be permitted, and the dopamine agonists are generally interrupted as soon as the pregnancy is confirmed.

3.
In patients with macroadenomas, even in the presence of a chiasmatic syndrome, dopamine agonists are the best primary treatment. Improvement in the visual disturbance is often very rapid, and tumor shrinkage is usually very significant. Thus, the results provided by dopamine agonists are generally much better than those obtained with surgery, even when it is performed by a highly skilled surgeon. If dopamine agonists are not rapidly effective, however, surgery is recommended. In such cases, if serum PRL levels remain high postoperatively (which is likely the case for macroadenomas, particularly when they are large), dopamine agonists are given. When pregnancy is planned in patients with macroprolactinomas, one might propose to pursue treatment with dopamine agonists during the entire pregnancy. Alternatively, before pregnancy, surgery may be selected with the goal of removing much of or the entire lesion. Thereafter, dopamine agonists are given to those patients with remaining hyperprolactinemia until the onset of pregnancy; at that time, the drugs are halted.

4.
Currently, radiotherapy is an option that is very seldom used. This treatment must be limited to the rare patients with large, incompletely resected tumors who continue to have high serum PRL levels, are resistant to dopamine agonists, and experience amenorrhea or mass effects of the lesion.
ADRENOCORTICOTROPIC HORMONE–SECRETING ADENOMAS
Most ACTH-secreting adenomas (90%) are microadenomas. The principal therapeutic difficulty caused by these lesions are their small size, which may hamper their preoperative visualization by imaging studies and their subsequent surgical resection. When a rare macroadenoma occurs, it usually is large and invasive; in such a case, total surgical resection may be difficult. Due to the poor prognosis of persistent hypercortisolism, adjuvant therapy with drug therapy is frequently required.
THERAPEUTIC OPTIONS
Transsphenoidal surgery and/or radiotherapy are the main therapeutic options; their techniques and side effects have been described.
Medical treatment has an important place as an adjuvant therapy.
Although a few case reports of cyproheptadine-induced remission of Cushing disease have been described, in the vast majority of patients no beneficial effect or only a moderate improvement has been observed with cyproheptadine administration,98 and its use has been abandoned.
Octreotide and lanreotide have no established place in the treatment of Cushing disease, although a few patients may respond with a decrease in ACTH secretion.98
Medical therapy in Cushing disease is currently limited to the use of compounds directed to the adrenal that are able to inhibit steroidogenesis (i.e., mitotane, ketoconazole, metyrapone, etomidate, trilostane, or aminoglutethimide).98,99 The adrenolytic agent mitotane (1,1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]-ethane or o,p’-DDD) inhibits 11b-hydroxylase and cholesterol side-chain cleavage enzymes and destroys adrenocortical cells. The drug is given orally at a dosage of 6 to 12 g per day. Principal side effects of mitotane are gastrointestinal symptoms (nausea, loss of appetite), hypercholesterolemia, and gynecomastia. Neurologic side effects and skin rashes rarely occur. True drug-induced hepatitis (with increased levels of serum transaminases), which requires discontinuation of the drug, is rare; this must be distinguished from increased levels of g-glutaryl transferase, which is frequent and benign and occurs in the setting of a fatty liver associated with the obesity of Cushing syndrome. Due to its marked liver enzyme–inducing effect, increased production of several binding proteins (in particular transcortin, the cortisol-binding globulin) occurs during mitotane therapy. Thus, the efficacy of the drug needs to be monitored; assessment should not be based on total plasma cortisol levels (which remain artifactually increased) but on free urinary cortisol or on salivary cortisol. These latter tests reflect the serum levels of the free, unbound cortisol. Doses of hydrocortisone given for replacement therapy, if required, may for the same reason show superior effects to those generally used for the replacement therapy of adrenal insufficiency. With prolonged administration at high doses, mitotane is able to produce permanent destruction of adrenocortical cells and result in glucocorticoid insufficiency; this may be associated with hypoaldosteronism (see Chap. 75).
Ketoconazole, an imidazole-derivative antimycotic agent, inhibits various cytochrome P450 enzymes, including the side-chain cleavage enzymes 17,20 lyase, 11b-hydroxylase, and 17-hydroxylase. Ketoconazole is administered at a dosage of 600 to 800 mg twice daily. Reported side effects are hepatitis, gynecomastia, and gastrointestinal symptoms. Another imidazole derivative, the anesthetic drug etomidate, when given intravenously at a nonhypnotic dose (3 mg/kg body weight per hour) has an immediate cortisol-lowering effect. Metyrapone, administered at a dosage of 2 to 4 g per day, inhibits 11b-hydroxylase and also may be used in the treatment of hypercortisolism. Nausea, vomiting, and neurologic symptoms are the most commonly reported side effects of metyrapone therapy. Aminoglutethimide (750 mg per day) inhibits several cytochrome p450 steroidogenic enzymes and efficiently controls hypercortisolism, but it may cause sedation, nausea, and rash; the same is true for trilostane (200–1000 mg per day), a carbonitrile derivative that inhibits conversion of pregnenolone to progesterone.
Except in the rare cases in which medical treatment is poorly tolerated or produces severe side effects (hepatitis), bilateral adrenalectomy is no longer used as therapy for Cushing disease because of substantial morbidity and mortality, the need for permanent replacement therapy with corticosteroids, and the subsequent (albeit low) risk for development of Nelson syndrome.
RESULTS OF TREATMENT
In the hands of skilled neurosurgeons, the apparent cure rate achieved by transsphenoidal surgery for Cushing disease due to microadenoma is 70% to 80%.98,100,101,102,103,104,105,106,107,108,109,110 and 111 The criteria for cure are an undetectable morning serum cortisol concentration and a plasma ACTH concentration of <5 pg/mL 4 to 7 days after surgery.101 Less strict criteria result in higher rates of apparent cure but a higher rate of recurrence (Table 24-6).

TABLE 24-6. Results of Transsphenoidal Surgery for Treatment of Cushing Disease

The recurrence rate of Cushing disease after surgery for a microadenoma is more frequent than was previously thought; a progressive upward trend is seen with time.103 In most series, the recurrence rate is 10% to 20% (see Table 24-6).
Only 50% of patients with macroadenomas achieve remissions after initial pituitary microsurgery.
In children, the rate of cure after transsphenoidal surgery is 70% to 86%104,112,113 and 114 and even reached 97% for one team.115 As is the case with adults, however, after extended follow-up and using the more stringent criteria now applied, these results will probably prove to be less favorable, probably in the range of 50% to 75%.113,114
In case of surgical failure, secondary irradiation therapy is able to produce remission in 56%116 to 83%117 of patients with Cushing disease after a median follow-up of ~3 years. Primary radiotherapy for Cushing disease is effective in 50% to 60% of adults and 85% of children.21,98,99,118
During the months or years required to achieve maximal benefits from irradiation, hypercortisolism usually can be controlled with adrenal enzyme inhibitors.98,99 After 8 months of therapy, remission of hypercortisolism is achieved in 83% of patients treated with mitotane. Combined with pituitary irradiation, mitotane produces remission of hypercortisolism in 80% to 100% of patients, but discontinuation of the drug leads to recurrence of the hypercortisolism in 30% to 50% of cases. Use of ketoconazole rapidly normalizes serum cortisol levels, but an escape from the effect of the steroidogenic agent is generally observed after a few months of treatment; this prevents long-term administration. Metyrapone is able to rapidly normalize plasma cortisol in 50% to 75% of patients with Cushing disease. Its interruption leads to recurrence of hypercortisolism. Aminoglutethimide only appears to be effective in controlling hypercortisolism in <50% of cases.
SUMMARY OF RECOMMENDATIONS FOR TREATMENT OF ADRENOCORTICOTROPIC HORMONE–SECRETING ADENOMAS
Table 24-2 summarizes the treatment decisions for Adrenocorti-cotropic Hormone–Secreting Adenomas.

1.
The primary therapy for children and adults is generally transsphenoidal surgery.

2.
Radiotherapy (50 Gy) is reserved for patients who have undergone only subtotal resection or who remain hyper-secretory after surgery.

3.
While one waits for the effects of radiotherapy, or if it is contraindicated, adrenal steroidogenesis inhibitors (in particular, mitotane) may be indicated.
THYROID-STIMULATING HORMONE–SECRETING ADENOMAS
THERAPEUTIC OPTIONS
Surgery and radiotherapy are the usual therapeutic tools for treating TSH-secreting adenomas. They have been described in detail earlier in this chapter.
Medical adjuvant therapy with somatostatin analogs has proven to be very useful. Octreotide and lanreotide are quite effective in reducing TSH levels in patients with TSH-secreting adenomas, thus allowing normalization of plasma thyroid hormone levels in a high proportion of patients.119,120 The associated side effects are similar to those of somatostatin analogs used in the treatment of acromegaly.
RESULTS OF TREATMENT
Forty percent of patients with TSH-secreting adenomas are not cured by surgery, even when it is combined with radiation therapy. In these patients, thyrotoxicosis persists.121
Octreotide, the somatostatin analog, is able to reduce serum TSH and a subunit levels in 91% of patients and normalizes thyroid hormone levels in 73% of patients.119 The reduction in tumor volume is similar to that obtained in acromegalic patients treated with octreotide. Lanreotide has very similar effects.120
SUMMARY OF RECOMMENDATIONS FOR TREATMENT OF THYROID-STIMULATING HORMONE–SECRETING ADENOMAS
Treatment decisions for TSH-secreting adenomas are summarized as follows:

1.
The primary therapy is transsphenoidal surgery, regardless of the size of the tumor.

2.
Irradiation therapy (40–50 Gy) is generally proposed only in the case of incomplete resection, particularly when the remnant is invasive.

3.
Somatostatin analogs are indicated in cases of persistent postoperative hyperthyroidism, while the effects of radiotherapy are being awaited.
CLINICALLY NONFUNCTIONING PITUITARY ADENOMAS
The majority of NFPAs are gonadotrope cell adenomas. Indeed, among all the types of macroadenomas, NFPAs are the most frequent. Despite their gonadotrope nature, as demonstrated by immunocytochemical staining, NFPAs are only rarely associated with increased levels of dimeric LH or FSH. However, increased levels of uncombined subunits (free a subunit primarily, LH-b subunit more rarely) are more frequently encountered but are generally modest in titer. The posttreatment assessment of cure usually is based on morphologic changes; hormonal monitoring is not usually helpful for this assessment. The main problems raised by NFPAs are the mass effects, mainly optic chiasm compression and/or deficient hormone secretion resulting from compression of normal anterior pituitary cells.
THERAPEUTIC OPTIONS
Surgery and radiotherapy are the only really effective therapeutic options available for NFPA; technical aspects and side effects have been discussed earlier.
Various medical treatments have been tried (i.e., administration of dopamine agonists, gonadotropin-releasing hormone [GnRH] analogs), but none has proven to be sufficiently effective as a reasonable therapeutic option. In occasional patients, the somatostatin analog octreotide may minimally improve visual defects due to chiasmal compression.122,123
RESULTS OF TREATMENT
The strategy of observation only for patients with incidentally discovered pituitary adenomas (incidentalomas) may be appropriate provided the tumor is well delimited, small, and has no suprasellar or lateral extension that risks neurologic or visual chiasm compression, and a meticulous hormonal work-up has ruled out the possibility that the hormonal hypersecretion is sufficient to produce a clinical syndrome.124 In all other cases, clinically evident, but apparently inactive, pituitary adenomas require surgery.
Transsphenoidal surgery allows improvement in visual disturbances due to chiasmal syndrome in 44% to 70% of patients.125,126,127,128 and 129 When the NFPA is a gonadotropin-secreting adenoma associated with supranormal levels of gonadotropins or free subunits, surgery almost always reduces supranormal plasma FSH and/or a subunit levels and normalizes them,129 despite the persistence of a tumor remnant. When an NFPA is responsible for pituitary failure, surgery is able to improve pituitary function in 15% to 50% of cases. On the other hand, surgery may aggravate the preoperative pituitary deficiency.
After surgery alone, nearly 30% (from 10% to 69%) of patients relapse within 5 to 10 years.10,25,125,127,129,130,131,132,133,134 and 135 variability in these data reflect differences in neurosurgical expertise, as well as the differing quality of the imaging techniques used postoperatively to assess the extent of tumor excision (Table 24-7).

TABLE 24-7. Recurrence Rate According to Therapy for Nonfunctioning Pituitary Adenomas

Radiotherapy is proposed either as a systematic adjunct or if a significant remnant persists. Use of systematic radiation therapy is supported by the low relapse rate (mean, 11%; range, 6%– 21%) that is observed when irradiation is routinely combined with surgery10,20,25,125,129,130,131,132,133,134 and 135 (see Table 24-7). However, irradiation is almost always followed by hypopituitarism, and several epidemiologic studies have demonstrated that postirradiation hypopituitarism might be associated with a reduction in life expectancy, despite appropriate replacement therapy136,137 and 138 (see Prognosis section).
Results of medical treatment are disappointing. Bromocriptine is not very effective in reducing levels of supranormal gonadotropins and free subunits, and only rarely produces a minimal tumor shrinkage.79,139 Somatostatin analogs are able to improve visual problems minimally in 20% to 40% of cases, but reports of reduction in tumor volume is anecdotal.122,123 Use of GnRH agonists is generally ineffective139 and may be hazardous.140 Prolonged administration of a GnRH antagonist to a small number of patients with a secreting gonadotrope cell adenoma has been reported to reduce supranormal gonadotropin levels but did not produce any change in tumor size.141
THERAPEUTIC RECOMMENDATIONS FOR TREATMENT OF CLINICALLY NONFUNCTIONING ADENOMAS
Table 24-2 summarizes recommendations for the treatment of NFPAs.
Transsphenoidal surgery with or without postoperative radiation therapy (50 Gy) is performed for almost all patients, irrespective of whether they have visual consequences of their tumor. Selected patients with small, incidentally discovered microadenomas may be carefully followed without immediate therapy.
PROGNOSIS OF PITUITARY ADENOMAS AND THERAPEUTIC PERSPECTIVES
PROGNOSIS
Prognosis depends on the type of tumor and a combination of other factors, including (a) the severity of the endocrinologic disturbance or mass-related symptoms and signs, (b) the size and extent of the tumor as indicated earlier, (c) the success of therapy in reversing these abnormalities, (d) morbidities due to therapy, and (e) permanence of the therapeutic response. Although pituitary tumors are generally benign, the failure to provide adequate therapy can lead to severe functional deficits and death. Optimal therapy can greatly improve quality and duration of life.
ACROMEGALY
If patients with acromegaly remain untreated, they have a 10-year reduction in life expectancy, in particular due to cardiovascular and respiratory problems and to the increased risk of neoplasms. The standardized mortality ratio (SMR, the observed mortality divided by the expected mortality in a sex- and age-matched control population) is from 1.8 to 3.46,48,49 and 50 The most important predictive factor of mortality is the “final” posttherapeutic serum GH level.46,47,48,49 and 50 When the “final” serum GH level is <2.5 µg/L, the mortality is not significantly different from that of the general population. When the final serum GH level is >2.5 µg/L, the SMR is between 1.4 and 2, which signifies a statistically different mortality from that of the general population. This indicates that application of the more stringent definition of cure or successful outcome in acromegaly which is currently used (i.e., serum GH levels of <2.5 µg/L) is probably associated with better survival than were the criteria previously used (i.e., serum GH <5 µg/L or <10 µg/L).
CUSHING DISEASE
The mortality in patients with Cushing disease is higher than that expected for the control population (SMR, 3.8; 95% confidence limits, 2.5–17.9). The most common cause of death is vascular disease. Advanced age, persistence of hypertension, and abnormalities in glucose metabolism after treatment are independent predictors of mortality.142
HYPOPITUITARISM
Hypopituitarism, particularly after surgery and/or radiation therapy for NFPA, is also associated with an increase in mortality (SMR, 1.70–2.10), according to the very concordant results of three studies.136,137 and 138 Death was reported to be due mainly to an increase in cardiovascular deaths in some studies136,137 and 138 but not in others137 (Table 24-8). GH deficiency was cited as a potential cause of the increased mortality in these patients; presumably, they were given adequate replacement therapy for other pituitary hormones but had not received GH-replacement therapy. This assertion remains highly questionable, however, because GH deficiency was not proven in all the patients in these studies and because often evidence was found of a long-term lack of pituitary hormones or of an inadequacy of hormonal substitution in many of them. GH treatment in patients with GH deficiency has been reported to be associated with numerous, albeit modest, increases in lean body mass, improved quality of life, amelioration of lipid abnormalities, and increased bone mineral content.143 However, whether or not a substitutive therapy with GH would improve the prognosis for hypopituitarism in adults is presently unknown.

TABLE 24-8. Epidemiologic Studies Demonstrating an Increased Mortality in Patients with Hypopituitarism

PROLONGED (LIFELONG) SURVEILLANCE
Regular assessment for many years of the pituitary function of patients treated for pituitary adenomas is essential to allow rapid adequate replacement therapy in patients who develop hypopituitarism. Hypopituitarism may occur up to 30 years after radiation therapy.
CONCLUSIONS AND PERSPECTIVES CONCERNING TREATMENT OF PITUITARY ADENOMAS
Although progress in imaging techniques has greatly improved the ease of diagnosing and localizing pituitary lesions, it has also been responsible for more frequent detection of incidental and clinically innocent lesions. The appropriate management of such pituitary incidentalomas, taking into account the cost, possible benefits, and complications of potential therapy, needs to be determined more precisely.
The early recognition of acromegaly, a condition that is responsible for important morbidity and cosmetic consequences, needs to be improved.
The management of pituitary adenomas is currently well defined. According to the type of tumor and the clinical situation, options include surgery, irradiation, and/or drugs.144
Surgical resection by the transsphenoidal route carries a very low morbidity and mortality. In skilled hands, it often allows a complete cure of the disease. Improvement is needed in surgical techniques to obtain a better removal of invasive tumors. Whether endoscopic techniques or the use of intraoperative MRI or intraoperative computer-assisted neuronavigation with robots would improve the outcome is presently unknown.
Diagnostic challenges are rare, except in the case of Cushing disease. Here, Cushing syndrome due to occult ectopic ACTH-secreting tumors (often bronchial carcinoids) may be misconstrued as being due to a nonvisible corticotropic microadenoma. This may delay appropriate treatment. Further improvements in imaging techniques are unlikely to allow better definition of these pituitary microadenomas. When Cushing disease is suspected, bilateral inferior petrosal sinus catheterization generally confirms or rules out a pituitary causation.
Histopathologic techniques (particularly immunocytochemistry) have greatly assisted the classification of pituitary adenomas. However, no markers of invasiveness or aggressiveness have been identified that can be routinely applied to tumor specimens removed at surgery. In this respect, prospective studies of molecular genetic alterations that have been demonstrated in pituitary adenomas144 will determine whether they are truly predictive of subsequent behavior and can be used to aid clinical management in a manner not possible with current histologic criteria. Conceivably, this may assist in decisions regarding which patients might need postoperative irradiation therapy.
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One comment on “CHAPTER 24 PITUITARY TUMORS: OVERVIEW OF THERAPEUTIC OPTIONS

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