2.3.12 Clinically nonfunctioning pituitary tumours and gonadotropinomas

The significant progress that has been made in the past years in the medical treatment of all pituitary adenomas is in stark contrast with the lack of progress in the medical treatment of clinically nonfunctioning pituitary tumours, or adenomas. In fact, only secreting, or functioning, tumours can be treated by medical therapy with at least modest to very impressive effect. Clinically nonfunctioning pituitary adenomas do not produce clinical signs of hormonal hypersecretion. Therefore, signs and symptoms will depend on the mass effect of these adenomas over the central nervous system (1–3).

Due to the lack of hypersecretion of hormones, nonfunctioning pituitary adenomas present themselves because of their mass effect and compression or destruction of surrounding tissues. This could also lead to hypopituitarism, which can be the presenting symptom as well (1–3). Despite their histologically benign nature, giant and ‘invasive’ nonfunctioning pituitary adenomas are one of the most complex neurosurgical challenges. Large nonfunctioning pituitary tumours are usually confined inferiorly by the sellar dura, superiorly by the elevated sellar diaphragm, and laterally by an intact medial wall of the cavernous sinus. If the anatomical extensions of the tumour are understood and a radical tumour resection is achieved, the visual and long-term outcome can be very rewarding. The goals of surgery are twofold: first to make a pathological diagnosis, and second, because these tumours are endocrinologically silent, to decompress the neural tissue (4). The vast majority of nonfunctioning pituitary adenomas are gonadotroph cell adenomas, as demonstrated by immunocytochemistry. However, they are rarely associated with increased levels of dimeric luteinizing hormone or follicle-stimulating hormone. Increased levels of subunits (free α-subunit mainly, LH-B subunit more rarely), however, are more frequently encountered, but are generally modest (5).

In this chapter the term ‘clinically nonfunctioning pituitary adenomas’ is used to describe pituitary tumours, which in most instances produce low quantities of hormones causing no clinically recognizable symptomatology. In the few instances, in which such tumours produce intact gonadotropins that activate testicular or ovarian activity, the term ‘gonadotropinomas’ is used.

In the late 1970s and early 1980s, much work has been done on defining the pathological properties of pituitary tumours (6–9). The work of Asa and Kovacs is specially known for the accurate description of the microscopic findings of nonfunctioning pituitary adenomas (10). These tumours are morphologically classified into two groups, those which have hormone immunoreactivity and ultrastructural features of known adenohypophyseal cell types but are clinically silent, and those composed of cells that do not resemble nontumorous adenohypophyseal cell types. Among the former are the silent somatotroph adenomas, silent corticotroph adenomas, and silent gonadotroph adenomas; the latter include the silent type III adenomas, null cell adenomas, and oncocytomas (10). It is now known that nonfunctioning adenomas represent a heterogeneous group. By immunocytochemistry, the large majority of these tumours are glycoprotein producing and less commonly they are nonfunctioning somatotroph, lactotroph, or corticotoph adenomas (10–19). Their aetiopathogenesis is complex and their development is probably influenced by several factors, such as hypothalamic hormones (growth hormone-releasing hormone), growth factors (fibroblast growth factor), proliferation factors (proliferative cell nuclear antigen and Ki-67), protein p53, and the proto-oncogene c-erb-B2 (20).

Gsp and MEN1 genes play a role in the initiation and promotion of pituitary adenomas, while p53, ras, Rb, and nm23 genes play some role in the progression of the tumour. Gsp gene may play an important role in activation of 10% of nonfunctioning tumours (21). Gsp produces cAMP, which later produce cdk2 and cdk4 respectively, and stimulates cell progression from G1 to S phase. cAMP also induces ras gene, which inhibits binding of pRb with E2F, which is necessary to prevent action of E2F in th eaccelerating cell cycle (21).

A substantial proportion of tumours with particularly aggressive behaviour are the so-called ‘silent subtype 3 adenoma’. Its diagnosis requires ultrastructural confirmation. Although once included among silent corticotroph adenomas, this aggressive, morphologically distinctive tumour is now recognized as a major form of plurihormonal adenoma and, in fact, some patients might present with clinical hormonal excess. In a recent report from the Mayo Clinics on 27 confirmed examples of silent subtype three adenomas, most of these tumours were plurihormonal, featuring immunoreactivity for PRL prolactin (n=17), growth hormone (n=15), thyroid-stimulating hormone (TSH) (n=16), or adrenocorticotropic hormone (ACTH) (n=3), while only 1 lesion was immunonegative (22).

Nonfunctioning pituitary tumours are relatively common. A large number of these tumours are incidentally found pituitary microadenomas (<1 cm) and are usually of no clinical importance. Those tumours that require treatment are generally macroadenomas and come to medical attention because of mass effect and/or hypopituitarism. Visual field defects are present in roughly 70% of patients with nonfunctioning macroadenoma at the time of diagnosis and the majority of these patients have at least growth deficiency and hypogonadism (3).

Hyperstimulation by excessive FSH secretion of gonadotropinomas has been described in only a few patients. An example of this is the observation of high serum FSH concentrations, but normal luteinizing hormone and testosterone and large testes in four men with pituitary macroadenomas (23). After pituitary surgery there were decreases in serum gonadotropin and testosterone levels, which were accompanied by decreases in testicular volume (23). In females, a similar example was the description of a woman whose gonadotroph adenoma caused supranormal serum concentrations of FSH, which resulted in the development of multiple ovarian cysts, persistent elevation of her serum oestradiol concentration, and endometrial hyperplasia (24).

Except for gonadotropins and their free subunits that may be increased in the case of gonadotropinomas, markers of endocrine secretory activity are lacking. In subjects with nonfunctioning pituitary adenomas, only 11% have elevated basal chromogranin A (CgA) levels, so serum CgA levels do not provide a helpful marker for the clinical management of these tumours (25). As stated in the introduction, the vast majority of nonfunctioning pituitary adenomas are gonadotroph cell adenomas, as demonstrated by immunocytochemistry. Increased levels of uncombined subunits are more frequently encountered, but are generally modest (5).

Sellar masses are associated most commonly with pituitary adenomas. Many other neoplastic, inflammatory, infectious, and vascular lesions, however, may affect the sellar region and mimic pituitary tumours. These lesions must be considered in a differential diagnosis of especially nonfunctioning pituitary adenomas (26). The diagnosis of such lesions involves a multidisciplinary approach, and detailed endocrinological, ophthalmological, neuroimaging, neurological, and finally histological studies are required (27). Examples of immune diseases that can present as nonfunctioning pituitary adenomas are sarcoidosis (28, 29), lymphocytic hypophysitis (30), plasma cell granulomas (31), and idiopathic granulomatous hypophysitis (32).

Relatively frequent encountered inflammatory lesions of the sellar region are isolated tuberculomas (33), while the wide spectrum of benign nonpituitary sellar tumours ranges in diagnosis from myofibroblastic tumours (34), ependymomas (35), osteochondromas (36), and pituitary blastomas (37) to paragangliomas (38) and angiolipomas (39). Malignant lesions are almost always metastases of which mammary cancer and prostate cancer are the most frequently observed ones (40). Probably the most frequent and important sellar lesion that is often confused with a nonfunctioning pituitary adenoma is the lymphocytic hypophysitis. Pituitary autoimmunity encompasses a spectrum of conditions ranging from histologically proven forms of lymphocytic hypophysitis to the presence of pituitary antibodies in apparently healthy subjects. Hypophysitis is a rare but increasingly recognized disorder that typically presents as a mass in the sella turcica. It mimics clinically and radiologically other nonfunctioning sellar masses, such as the more common pituitary adenoma (41). Hypophysitis shows a striking temporal association with pregnancy (42), and it has been recently described during immunotherapies that block CTLA-4. Several candidate pituitary autoantigens have been described in recent years, although none has proven useful as a diagnostic tool (41).

Hypophysitis has been histologically classified into five types: lymphocytic hypophysitis, granulomatous hypophysitis, xanthogranulomatous hypophysitis, xanthomatous hypophysitis, and necrotizing hypophysitis (43).

Therapeutic modalities for nonfunctioning pituitary adenoma include surgery, radiotherapy, and medical therapy. In patients with relatively small adenomas, i.e. intrasellar adenomas or adenomas with limited extrasellar extension, a wait and see policy can be applied with careful radiological follow-up (44). Microadenomas (<10 mm) rarely grow and convert to a macroadenoma (45, 46). Macroadenomas, in contrast, tend to grow and the tumour volume of macroadenomas increases gradually in approximately 50% of patients (14, 47). In patients with a growing adenoma or with complications due to mass effects of the tumour, surgery is indicated eventually followed by radiotherapy and/or medical therapy.

Suprasellar and parasellar extension of nonfunctioning pituitary adenoma can lead to compression of the optic chiasm and the ophthalmic motor nerves (cranial nerves III, IV, and VI), respectively, which can result in a decreased visual acuity, temporal visual field defects and ophthalmoparesis. The aims of pituitary surgery for nonfunctioning pituitary adenoma are recovery of visual function, to obtain tumour tissue for pathological diagnosis, and to achieve long-term tumour control. Urgent decompression is indicated in patients with a pituitary apoplexia, a syndrome caused by acute bleeding and/or infarction of the adenoma resulting in a sudden tumour expansion with acute visual loss and cranial nerve palsy. Pituitary surgery is primarily performed by the transsphenoidal approach (Fig. 2.3.12.1) (48). Also tumours with a large suprasellar component can successfully be resected via the transsphenoidal route. A transcranial approach via the pterional or subfrontal route may be indicated in case of a dominant extrasellar tumour compartment and a small sella turcica, a large eccentric tumour extension into the middle, anterior or posterior cranial fossa, or a coexisting aneurysm of the carotid artery (49). Transcranial surgery is, however, accompanied by a higher morbidity and mortality rate compared with the transsphenoidal approach (49).

After transsphenoidal resection, improvement of visual function is achieved in 85–90% of patients with normalization of vision in approximately 40% of patients (50, 51). The rapidity of visual recovery depends in part on the duration of optic nerve compression. Recovery of visual function can already be observed in the first days postoperatively and can continue up to a year after surgery (52–54). In patients with pre-existing (partial) hypopituitarism, pituitary function is not likely to restore after resection of the adenoma although in some patients improvement can be demonstrated (44, 55). In experienced hands, transsphenoidal surgery is a safe procedure with a perioperative mortality of 0.5–1% (56). Postoperative complications are cerebrospinal fluid leakage, meningitis, (transient) diabetes insipidus, and new anterior pituitary deficiency (48). Recent developments in pituitary surgery include the endoscopic approach and the use of neuro-navigation and intraoperative MRI (48, 57). Advantages of endoscopic surgery are a wider and closer view of the surgical area, also of the supra- and parasellar regions, and less nasal traumatism with no need for postoperative nasal packing (57). Future studies will reveal whether these new techniques will improve surgical outcome.

Complete removal of a macroadenoma is achieved in only a minority of patients. The optimal treatment strategy of patients with a residual tumour after transsphenoidal surgery (example shown in Fig. 2.3.12.1b) is still a matter of debate. Observational studies on the natural course of macroadenoma remnants show variable results with tumour regrowth rates between 6% and 46% (50, 58–62). Factors predictive of regrowth are parasellar invasion before surgery and (the degree of) suprasellar extension of the postoperative remnant adenoma (62). Unfortunately, no morphological tumour features or molecular markers of cell proliferation are available that predict tumour growth (63, 64). Postoperative external radiotherapy is applied in nonfunctioning pituitary adenoma to achieve long-term tumour control by induction of tumour shrinkage or stabilization. In patients who receive conventional radiotherapy, progression free survival at 10 years is more than 90%, significantly higher compared to patients who where only observed (65–68). On the other hand, radiotherapy can not control tumour growth in each patient. Studies vary with respect to follow-up duration, amount of invasive tumours, etc., but regrowth of residual adenomas in patients treated with radiotherapy has been observed in 2–36% of patients (50, 61, 62). Overall, although no randomized trials have been performed that compare radiotherapy with a wait and see policy. Adjuvant radiotherapy has beneficial effects on tumour regrowth but this should be balanced against the complications of radiotherapy, i.e. radiation damage to the optic nerves with visual impairment, development of (partial) hypopituitarism in up to 50% of patients, increased risk of cerebrovascular events and an increased risk on secondary brain tumours (65, 69–73). Therefore, the treatment strategy in patients with a residual adenoma after transsphenoidal surgery should be individualized and factors such as age, comorbidity, remnant tumour size, tumour distance to the optic chiasm, and status of pituitary function should be involved in the decision on adjuvant radiotherapy. Patients not treated with radiotherapy should carefully be observed with MRI and ophthalmological evaluation. If regrowth occurs, radiotherapy is still effective, but repeat surgery can also be considered (74).

Stereotactic radiotherapy is a more recently developed radiation technique with radiosurgery and fractionated stereotactic radiotherapy as treatment modalities (75). The advantage of stereotactic radiotherapy is that more accurate tumour localization is achieved with consequently less exposure of surrounding brain tissue to radiation. With radiosurgery a high-dose focused radiation is given in a single treatment session. Radiosurgery is suitable for small adenomas with sufficient distance to the optic nerves and optic chiasm which are radiosensitive tissues. Fractionated stereotactic radiotherapy can be applied in larger tumours and tumours with a smaller proximity to the optic chiasm (75). With both forms of stereotactic radiotherapy tumour control can be achieved in more than 90% (76–79). No data are available yet that compare recurrence rates and long-term safety and complications of conventional radiotherapy and stereotactic radiotherapy.

In analogy with medical treatment of prolactinomas and somatotroph pituitary adenomas, the possibility of medical treatment in patients with clinically nonfunctioning pituitary adenomas has been investigated. Several different drugs (combinations) have been investigated.

Clinically nonfunctioning pituitary adenomas express dopamine receptors on their cell membranes (1, 80). The D₂ receptor is the predominantly expressed subtype, and mainly as its long version (D₂ long, D₂Lh). The D₂ short isoform (D₂Sh), or combinations of both D₂Lh and D₂Sh isoforms are expressed in a minority of cases. The D₄ receptor can also be expressed by these tumours (81–83).

Based on these findings, the effects of various dopamine agonists have been investigated in these tumours, both in vitro and in vivo. Addition of high pharmacological concentrations of bromocriptine, quinagolide, or cabergoline to cultures of tumour cells of gonadotroph origin suppressed the release and synthesis of gonadotropins and their α-subunits (82, 84). These results closely correlated with D₂ expression on the tumour cells (82).

In patients with nonfunctioning pituitary adenoma, dopamine agonist therapy causes tumour shrinkage in approximately 28% of patients. There is, however, a huge variation in this response between the different studies, depending on patient’s selection, size of the study population (generally very small), choice of the dopamine agonist and its dose and the treatment period (82, 85–101). The results of the different studies are shown in Table 2.3.12.1. In line with this observation of tumour shrinkage occurring in selected cases, improvements in visual field defects have also been observed in a similar percentage (20%). Tumour growth was observed in 9% of cases (Table 2.3.12.1).

D₂ receptor scintigraphy of pituitary adenomas is feasible by single photon emission computed tomography (SPECT) using ¹²³I-S-(–)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-hydroxy-3-iodo-6-methoxybenzamide (¹²³I-IBZM) and ¹²³I-(S)-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-iodo-2, 3-dimethoxybenzamide (¹²³I-epidepride) (Fig. 2.3.12.2). ¹²³I-epidepride is superior to ¹²³I-IBZM for the visualization of D₂ receptors on pituitary macroadenomas (102–104). Although it was initially suggested that D₂ receptor scintigraphy might be a useful tool for predicting inhibition of hormonal hypersecretion and tumour shrinkage by dopamine D₂ agonists in patients with clinically nonfunctioning adenomas, more recent studies could not confirm these results. However, there seems to be a correlation between the intensity of the tumour uptake of the radioligand and tumour shrinkage with dopamine agonist treatment (97, 98, 105). These findings are in line with studies showing a positive correlation between dopamine D₂ expression in surgically removed tumour tissue and postoperative tumour remnant shrinkage with cabergoline (82). The postsurgery use of dopamine agonists to prevent tumour regrowth of nonfunctioning pituitary adenoma is, therefore, also advocated by other experts in the field (101, 106).

Somatostatin receptors are expressed in nonfunctioning pituitary adenoma, with a predominance of the somatostatin receptor subtype 3 (sst₃), followed by sst₂ and sst₅ and infrequent expression of sst₁, sst₄ and sst₅ (107–109). The expression of sst₂ is required for achieving a tumour response to the currently available octapeptide somatostatin analogues, octreotide and lanreotide. These drugs show a high affinity for sst₂ and sst₅ and a low affinity for sst₃ and no affinity for sst₁ and sst₄ (110, 111). Both somatostatin analogues have demonstrated promising results in vitro with regard to their effects on growth of cells derived from nonfunctioning pituitary adenoma and suppression of their secretory products (112–114).

The effects of immediate release octreotide on the size and secretion of clinically nonfunctioning pituitary adenomas have been tested in several clinical trials (115–123). The study results are summarized in Table 2.3.12.2. Like in the trials studying the effects of dopamine agonists, a huge variation in tumour and/or biochemical response between the different studies, depending on patient’s selection, size of the study population (generally very small), and dose and treatment period existed. Medication was either given as primary therapy or as adjuvant therapy. Tumour reduction was reported in 3% of cases. The great majority of patients (86%) had stable (remnant) tumours (Table 2.3.12.2). In 11% of the patients tumour (re-)growth was observed despite treatment.

¹¹¹In-pentetreotide scintigraphy (OctreoScan) has been used for demonstrating the presence of the sst₂ subtype on pituitary adenomas. In contrast with dopamine receptor scintigraphy, the normal, nonpathological, pituitary can also be visualized as a receptor-positive area using this technique. This might partly explain the contradictory findings obtained by using this imaging technique in different studies in patients with nonfunctioning pituitary adenoma for predicting the effects of somatostatin analogues on these adenomas (120, 122–125). ¹¹¹In-pentetreotide scintigraphy is generally not recommended and also not required for the clinical work-up of a clinically nonfunctioning pituitary macroadenomas. Interestingly, improvement in headaches and visual disturbances generally occurring shortly after introduction of octreotide treatment and despite the absence of a clear tumour response has been reported in two studies. This effect is more likely caused by a direct effect of this drug on the retina and the optic nerve (115, 116, 126).

Recently a new, so-called universal, somatostatin analogue has been introduced for clinical use. Pasireotide (SOM230) is a somatostatin analogue with high binding affinity to sst₁, sst₂, sst₃ and sst₅. In vitro, this drug was able to inhibit the viability of nonfunctioning pituitary adenoma cells by inhibiting vascular endothelial growth factor (VEGF) secretion (127). Of now, in vivo data with this promising compound are lacking.

In line with monotherapy with somatostatin analogues or dopamine agonists, combinations of both drugs in patients with nonfunctioning pituitary adenoma can also produce tumour shrinkage and improvement of visual field defects (128, 129). A new chimeric D₂ agonist/sst₂ and sst₅ analogue, BIM-23A760, was effective in inhibiting cell proliferation in two-thirds of clinically nonfunctioning pituitary adenomas in vitro (80, 130, 131). Until now, no clinical trials in patients with nonfunctioning pituitary adenoma have been performed with this promising new drug.

The release of gonadotrophins by normal anterior pituitary cells is regulated by pulsatile secretion of gonadotropin-releasing hormone by the hypothalamus. The chronic administration of gonadotropinreleasing hormone to normal individuals produces an initial rise in gonadotropin levels, followed by gonadotroph desensitization, leading to efficient suppression of gonadotrophin release. Several case reports describe the occurrence of pituitary apoplexy after the administration of gonadotropinreleasing hormone as a test agent or as an agonist for the treatment of prostate cancer (132–137). Long-term treatment with gonadotropinreleasing hormone analogues had no effect on tumour size or visual fields in patients with nonfunctioning pituitary adenoma (138, 139). This treatment modality is currently not anymore under clinical investigation.

Temozolomide has been proposed as a treatment option for pituitary carcinomas and aggressive pituitary adenomas. In addition, it has been suggested that the responsiveness of pituitary tumours to temozolomide depends on the expression of O(6)-methylguanine DNA methyltransferase (MGMT). A recent study has shown that in patients with progressive, regrowing nonfunctioning pituitary adenoma, about half of these tumour cells exhibited low MGMT expression and, therefore, are potential candidates for treatment with temozolomide (140).