Most pituitary adenomas produce elevated serum levels of one or more anterior pituitary hormones; these include adenomas secreting growth hormone (GH), adrenocorticotropic hormone (ACTH), prolactin, follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH). These are called secretory pituitary adenomas. Nonsecretory pituitary adenomas constitute a loosely defined group that includes the pituitary tumors that remain when the tumors noted above are removed from consideration; they are associated with normal or low serum levels of GH, ACTH, prolactin (usually, but see below), FSH, and TSH. They are also called nonfunctional, clinically nonfunctioning, silent, and endocrine-inactive adenomas, and generally correspond to the pathologic diagnoses of null-cell adenoma and oncocytoma.
Our growing understanding of pituitary pathophysiology has led to a steady diminution in the number of pituitary adenomas considered to be nonsecretory. In the nineteenth century, Pierre Marie and Paul Broca described acromegaly and then related it to a pituitary mass. In the early part of the twentieth century, Cushing associated hypersecretion of ACTH with a basophilic pituitary adenoma. Hyperprolactinemia was identified after the development of immunoassays in the latter half of the twentieth century. Now tumors with clinically assayable hypersecretion of the glycoprotein hormones TSH, FSH, and luteinizing hormone (LH) or their subunits have been separated as well. The separation of these specific hypersecretory adenomas is a tribute to the power of modern endocrinology and the pivotal role of immunoassay techniques in understanding pituitary adenomas. One importance of finding a secretory product in serum is that it allows a hormonal test of tumour activity for follow-up.
Nonsecretory tumors comprise about 40 percent of adenomas in most surgical series. In imaging, they may resemble other lesions around the pituitary such as craniopharyngiomas, meningiomas, and intrasellar cysts, as discussed below; the correct diagnosis may be made only at surgery.
There are four common clinical presentations for a non secretory pituitary adenoma: visual blurring, headache, loss of libido, or absence of symptoms. Tumors may be surprisingly large for the relatively mild symptoms they produce.
Visual symptoms are found in 60 to 70 percent of cases, usually as loss of the temporal field in one or both eyes, loss of visual acuity, or vague blurring of vision. The early stages of peripheral field loss may not be noticed by the patient, and there may be rather substantial deficits on neuroophthalmologic testing at the time of tumour diagnosis. More common than field loss is non-specific blurring of vision, which may bother the patient with reading. This may not be detected on formal testing but is a definite and common symptom related to visual pathway compression. Diplopia or evident extraocular muscle weakness is rare, and should raise the possibility of a metastatic tumour or pituitary apoplexy rather than a routine non secretory pituitary adenoma no matter how large.
Headache is found in about 40 percent of patients. It is often non-specific and is felt primarily in the vertex as a dull ache that is constant and does not vary with position or time of day. Most often it is not incapacitating but is a definite symptomatic change for the patient. A rare but important headache syndrome in nonfunctioning adenomas is found in pituitary apoplexy. This presents with severe, sudden headache accompanied by neck stiffness and prostration; it may resemble subarachnoid haemorrhage. It is important to recognize this syndrome, because computed tomography (CT) done as the initial diagnostic procedure may not detect the adenoma owing to bony artefact at the skull base or to incomplete evaluation by the person interpreting the scan. Magnetic resonance imaging (MRI) should be performed if this condition is suspected.
Loss of libido is found most often in men. There may also be other symptoms and signs of panhypopituitarism in either men or women, with amenorrhea, sexual disinterest, smooth, pale skin, and chronic fatigue. These clinical findings are supported by base-line hormone levels that indicate significant pituitary insufficiency.
Some nonsecretory pituitary adenomas today present as a sellar or suprasellar mass found incidentally on a CT or MRI scan obtained to evaluate a head injury or other unrelated problem. The management of a patient with this finding requires considerable judgment and skill, as it is hard to make the patient's symptoms better by any treatment. If there is a danger of optic nerve compression or extension into the cavernous sinus, however, or if there is a likelihood of pituitary gland compression, transsphenoidal surgery is indicated unless there is a medical contraindication.
Apparently nonfunctioning adenomas may be associated with abnormal results on serum endocrine studies; these studies should be done as part of the comprehensive workup of an apparently nonsecretory lesion. Baseline endocrine testing includes assays of serum prolactin, growth hormone, cortisol, triiodothyronine (T3), thyroxin (T4), FSH, and LH. If the alpha subunit can be easily tested, it should also be measured.
There is currently discussion over the need for preoperative stimulation studies. Although such studies may be instructive, it is probably more important to obtain them postoperatively, as the results may change after surgery. The use of these tests depends in large part on the endocrinologists with whom the pituitary surgeon collaborates.
Prolactin may be elevated because of stalk compression in a non secretory adenoma. This occurs because prolactin secretion is regulated mainly by the inhibitory action of dopamine, which is released into the portal system of the pituitary stalk. Compression of the stalk impedes the transfer of dopamine, leading to an increased release of prolactin from pituitary lactotropes. A large sellar and suprasellar tumour with a prolactin level less than 200 ng/ml is more likely to be a nonfunctioning adenoma than a prolactinsecreting one. A trial of bromocriptine may be helpful in establishing that the tumour is non secretory, but if there is visual compression, a better alternative is surgical decompression and immunohistochemistry to establish the diagnosis.
Growth hormone and cortisol levels will usually be normal in patients on baseline testing but may show an abnormal lack of response to stress testing. Failure of growth hormone to rise during an insulin tolerance test or of ACTH and cortisol to rise during injection of corticotropin-releasing factor are suggestive of hypofunction of the pituitary.
FSH, TSH, and LH may be elevated in apparently non secretory pituitary adenomas, as the clinical symptomatology of these hypersecretion syndromes is mild. A measurable elevation of these hormones in serum places the tumour in the category of glycoprotein secreting tumors, rather than non secretory adenomas. Tumors with this hypersecretion have the advantage of being associated with measurable serum changes, so they can be followed easily. Hypersecretion of the alpha subunit associated with glycoprotein hormones is also found in a substantial fraction of patients with apparently "nonsecretory" adenomas. Using a sensitive monoclonal assay, Oppenheim and colleagues reported that 37 percent of patients with clinically nonfunctioning adenomas had elevated levels of the alpha subunit in their serum.
Low levels of FSH and LH may be an important early sign of hypopituitarism associated with a nonsecretory adenoma. Looking at a series of 26 patients with large nonfunctioning adenomas, Arafah found GH deficiency in 100 percent of patients, hypogonadism in 96 percent, hypothyroidism in 81 percent, and adrenal insufficiency in 62 percent. Prolactin levels were low in 5 patients, normal in 9, and elevated in 12. Unless there are symptoms of diabetes insipidus, it is not worth doing water deprivation tests or other tests of posterior pituitary function, even with large nonsecretory adenomas.
Postoperative endocrine testing is an important component of the ongoing evaluation of a patient. It should be postponed until acute surgical effects have passed, usually at least 2 weeks after operation. It should also include both baseline and stimulation studies.
Formal visual field and acuity testing are important in the evaluation of a patient with a nonfunctioning adenoma, especially if imaging studies show the tumour reaching the chiasm. The most usual finding is blurring of the temporal fields, but homonymous hemianopia from tract compression, enlarged central scotoma, and visual acuity loss are also possible. El Azouzi and colleagues found that 68 percent of patients with visual symptoms and a pituitary tumour had bitemporal field defects, but 5 percent had homonymous hemianopia because of retrosellar extension of tumour and compression of the retrochiasmatic optic system. It is important to recognize optic atrophy preoperatively because it suggests that recovery of visual acuity will not be complete in the affected eye.
Postoperative ophthalmologic follow-up should be carried out if there was a preoperative visual deficit but may not need to be a regular part of the long-term management if the patient has no visual symptoms and imaging studies show resolution of chiasmal compression.
By far the most useful imaging study for a pituitary adenoma is MRI. Scanning should be done without and with gadolinium contrast administration and in coronal sagittal, and transaxial planes. MRI can demonstrate the configuration of the tumour, exclude an aneurysm. establish the degree of retrosellar or parasellar extension. and indicate the internal architecture of the tumour, including whether it is cystic or contains haemorrhage.
On MRI non secretory pituitary adenomas are usually associated with an enlarged sella turcica. It is worth noting the pattern of extension of the tumour; if there is substantial enlargement of the sella and the tumour has a smooth suprasellar contour, there is likely to be an intact diaphragma sellae that will allow vigorous curetting; if the sella is modestly enlarged and the tumour appears to "spill over" into the suprasellar region, care should be taken in curetting above the sella. If there is major lateral extension to the cavernous sinus, resection via a transsphenoidal or any other route will be incomplete, and the surgeon should recognize this fact from the beginning.
If a patient is unable to have an MRI because of extreme claustrophobia or the presence of a pacemaker or other ferromagnetic prosthesis, CT without and with contrast enhancement may be used instead. CT scanning should be done in coronal as well as transaxial planes. Skull tomograms are not useful when CT or MRI can be done. Similarly, an angiogram is not necessary if MRI is available. If MRI cannot be performed, however, and the lesion has a regular ovoid or spherical shape in the suprasellar region on CT, angiography may be indicated to exclude an intrasellar aneurysm.
Differential Diagnosis of a Nonsecretory Pituitary Adenoma
There are a number of sellar and suprasellar lesions that may resemble nonsecretory adenomas on imaging. These can be divided into two types: masses of pituitary origin and masses of nonpituitary origin.
Among pituitary lesions that may resemble a non secreting adenoma clinically are prolactinomas and FSH- or LH-secreting adenomas. A prolactinoma may present as a large mass with no hormone elevation except for prolactin. With a large prolactinsecreting tumour. serum prolactin is usually elevated into the thousands of nanograms per millilitre. If the prolactin level is less than 200 ng/ml and the tumour is larger than 1 cm in diameter. the tumour is most likely a nonsecretory adenoma. A trial of bromocriptine treatment may also help in distinguishing a prolactinoma from a nonsecreting tumour; if the tumour shrinks dramatically in response to 5 to 10 mg of bromocriptine a day. it is most likely prolactinsecreting. About 20 percent of nonfunctioning adenomas show some response to bromocriptine, however. It is important to be aware of this possibility and to use regular imaging studies as well as endocrine testing in following tumors of this description, as otherwise one may be unaware that a presumed "prolactinoma" is continuing to grow despite low prolactin levels.
Other pituitary tumors that may resemble nonfunctioning tumors are those that produce FSH and LH or alpha subunit. These tumors can be identified with appropriate hormone testing and can be followed by both imaging and hormonal testing. Rarely, a pituitary abscess will resemble a non-secretory pituitary adenoma. There may be few symptoms associated with this.
The nonpituitary lesions that may resemble pituitary adenomas on imaging can be divided into benign tumors, malignant tumors, cysts, and miscellaneous lesions. Among the benign tumors are meningiomas and craniopharyngiomas. Meningiomas usually arise from the tuberculum sellae or the dura of the pituitary fossa. They are homogeneous in consistency and enhance brightly: close MRI examination may show an intact pituitary beneath them. They also tend to flatten at the base and there may be associated hyperostosis of the tuberculum sellae. Craniopharyngiomas are cystic or inhomogeneous lesions that may occupy the entire sella or expand above it; they may show calcification on CT. It is relatively unusual for a pituitary adenoma to be cystic, although old haemorrhage may make it so.
It may be difficult to distinguish craniopharyngiomas or cystic nonfunctioning pituitary adenomas from other cystic lesions. Rathke's cleft cysts. arachnoid cysts. and non-specific epithelial cysts may occur in the pituitary or in its stalk. Rathke's cleft cysts are homogeneous lesions of the stalk and are usually asymptomatic. Arachnoid cysts have the same absorption characteristics as cerebrospinal fluid. Epithelial cysts may be difficult to distinguish from nonfunctioning adenomas except by surgical exploration.
A number of malignant tumors may also occupy the sella, and it is important to consider them if a conservative approach is taken to a pituitary mass. Primary malignancies that may occur around the sella include chordomas and chondrosarcomas (which are usually distinguished by the presence of bony erosion and of calcification in a less dense matrix), malignant gliomas of the posterior pituitary gland, and an unusual tumour called granular cell myoblastoma, which appears to arise from embryonic tissue in the sellar region. Metastatic tumors may occur in the pituitary fossa and are radiologically indistinguishable from pituitary adenomas. The most common sites of origin are breast and lung. The best differential point in their diagnosis is their tendency to produce diabetes insipidus and/or eye movement weakness early in their course.
Pathology and Pathophysiology
The glycoprotein hormones are distinguished by their protein structure, with a common alpha subunit and distinct beta subunits that give each hormone its characteristic activity. An important initial step in the understanding of nonsecretory adenomas was the observation that most of them stain for the glycoprotein hormone subunits by immunohistochemical techniques; this has been shown to be true of the messenger ribonucleic acid (mRNA) for these subunits as well. However, the subunits produced by these tumors do not seem to be able to combine to provide receptor activation as normal pituitary hormones do, There are also fragments of other hormones in clinically nonsecretory adenomas: growth hormone production may occur; mRNA for prolactin and ACTH can be found in a small number; and a compound called chromogranin A may be an important assayable compound in these adenomas.
The study of clinically non secretory adenomas in culture has been an intriguing lesson in pituitary physiology. Kwekkeboom and colleagues demonstrated that, although most of these tumors released gonadotropins or their subunits in vitro, they usually did not do so in vivo, and responses to TRH and bromocriptine did not depend on baseline hormone levels.
The molecular biological origin of these tumors has not been easy to elucidate. They appear to be monoclonal in origin. Activated forms of G protein do not appear to be crucial in their initial development. Platelet-derived growth factor, a growth factor important in a number of human tumors, does not appear to be important for pituitary adenomas.
Possible treatments for non secretory pituitary adenomas include observation, medical treatment, surgery by either the transsphenoidal or the cranial route, and radiation therapy.
Small, silent pituitary adenomas may be treated by observation only; their natural history cannot be predicted, but MRI permits close follow-up. Asymptomatic pituitary masses less than 5 mm in diameter can be followed initially with MRI scans.
Treatment with a dopamine agonist such as bromocriptine has had variable success for nonsecretory adenomas. Sassolas and colleagues reported some shrinkage of tumour in 15 percent of patients receiving this treatment, but nothing like the dramatic shrinkage seen with prolactinomas.
Based on stimulation and inhibition studies of human tumors in culture, Klibanski and colleagues have suggested that somastatin inhibits intact glycoprotein or subunit secretion in most clinically nonfunctioning pituitary tumorsl4; perhaps a somatostatin analogue will be a useful agent if it can be made pharmacologically stable.
The treatment of choice for non secretory pituitary adenomas larger than 10 mm is surgical resection. Almost all pituitary adenomas can be treated initially by transsphenoidal surgery. Exceptions are tumors that are associated with a relatively small sella turcica or that have major parasellar or presellar extension. In these cases, transcranial surgery is a better approach.
The reason for frequent using of the transsphenoidal approach is the fact that complete removal of most of these tumors is impeded by cavernous sinus involvement. Tumors in the sinus cannot be removed with satisfactory morbidity by either the transcranial or the transsphenoidal approach, so the less morbid transsphenoidal resection is to be preferred.
For the transsphenoidal approach, an arterial line is usually not used, a lumbar drain is not inserted, and the patient receives hydrocortisone and antibiotics during anaesthesia induction. Approach to these tumors transnasally, carrying out the entire procedure using the operating microscope. The patient is positioned supine with head elevated slightly and turned 30 degrees to the right. A C-arm fluoroscope is used to visualize the sella. The operating microscope is brought in from the beginning. The skin of the nose and right lower abdominal quadrant are prepared with Betadine. The nasal mucosa is infiltrated with 1:400,000 epinephrine/0.5% xylocaine and incised along the left nasal septum starting just behind the mucocutaneous junction. A mucosal flap is elevated with a caudal dissector. The septum is cracked from left to right just in front of the sphenoid prow, but is not removed. A nasal speculum is placed, and the sphenoid prow is removed by chisel, taking care to produce a large enough fragment to close the sella. The floor of the sella turcica is drilled with a high-speed air drill or, if it is enlarged and thin, is opened with micro-pituitary rongeurs. The sella is opened widely-to the cavernous sinuses bilaterally and to the horizontal plane inferiorly. The dura is coagulated by touching a metal suction tip with a Bovie electrocoagulator on low power and is opened in an H shape or as a window. If bleeding from venous dural sinuses is encountered, it can usually be stopped by packing with Surgicel and applying compression for several minutes. Allowing the sinus to close by opening the dura more widely may also facilitate haemostasis. It is very important to achieve a dry field at this time.
Tumour resection should begin with the posterior and inferior portion of the tumour, gently using a variety of sizes and shapes of curette. A non secretory tumour is usually not hard to identify because it is usually a large mass. There may be a layer of normal anterior gland in front of the tumour, but there is usually no choice but to open through this.
If the opening in the sella is made too low, the posterior lobe may be mistaken for tumour and resected. The posterior lobe is pale white and soft; large tumors usually destroy it, but with tumors less than 1.5 cm in diameter it may still be present.
If there is considerable bleeding from the tumour, visible sources should be coagulated with the bipolar cautery or gently packed with Surgicel and a cottonoid patty; usually the bleeding will stop with time. Special attention should be paid to the inferior aspects of the tumour at this time; it is disappointing to spend a long time on the suprasellar extension of a tumour and then see a large inferior residual on postoperative MRI. The lateral pillars of the tumour should gently be removed next; sometimes these are firm and unyielding, but every attempt should be made to remove them to allow the suprasellar tissue to collapse into the sella. Care should be taken to avoid injuring the carotid arteries and cavernous sinus during this manoeuvre. A preoperative review of the MRI scans is important to assess how significantly tumour surrounds the arteries. If the tumour is very fibrous, it may be difficult to dissect it from surrounding tissue. The superior aspect of the tumour is left to last; if there is residual pituitary, it is usually possible to dissect the tumour away from it easily, and usually it is found packed against the back wall of the sella.
Pathologic examination has varying usefulness in demarcating tumour from normal gland. If the pathologist is experienced and can work quickly, a frozen section may be very helpful, but in many cases the surgeon is forced to rely on his or her surgical judgment.
The management of the diaphragm a sellae is sometimes problematic. If tumour is adherent to it, it should be removed even if there is a resulting cerebrospinal fluid (CSF) leak. If CSF is seen at the time of surgery, the sella is packed with fat harvested from the right lower quadrant; a fragment of sphenoid prow is inserted into the sellar opening; and fibrin glue made with autologous serum is used to seal the sella. A Valsalva manoeuvre is used to test for further leaking.
A number of techniques have been suggested for sealing an obvious and serious leak. One is to use fascia lata and fat to obliterate the sella. Our practice is to obliterate the sphenoid sinus with a combination of fat and oxidized cellulose cotton. Packs of bacitracin-coated finger cots or those with a nasal airway in them are placed in the nostrils, and the patient is maintained on antibiotics for 72 h while the packs are in place. Care must be taken to be sure that the mucosal flap is replaced over the septum. The patient is allowed to go home on the fourth postoperative day with maintenance steroids. Postoperative MRI is done either within 48 h or after 1 month.
Results of Surgery
The success of surgery for non secretory adenomas can be measured with four parameters: improvement in vision, improvement in endocrine function, radiographic removal of tumour, and paucity of complications. The literature gives data on the success of transsphenoidal surgery by each of these criteria. Sassolas and colleagues reported improvement in vision in 80 percent of patients and radiographically complete removal of the tumour in 70 percent. In 20 percent there was evidence of continued growth even after radiation therapy. Improvement in vision in 72 percent, diminished endocrine function compared with the preoperative level in 3 percent, and complete radiographic removal in 66 percent. Endocrine improvement may be expected in about two-thirds of patients. The preoperative response to thyroid-releasing hormone (TRH) was an important predictive test.
Complications of Surgery
Transsphenoidal surgery should only be done by a surgeon familiar with the technique, since major morbidity may result from the smallest deviation from a safe path. Among the potential dangers are persistent CSF leakage, injury to the carotid artery, damage to the midbrain or pons, haemorrhage in the sella turcica, loss of anterior pituitary function, and diabetes insipidus. Each of these has less than a 1 percent likelihood of occurring, but any of them can be devastating.
The most common complication is a CSF leak, which occurs in about 3 percent of patients. Every effort should be made to avoid this problem, as noted above. A lumbar drain should be inserted if there is postoperative evidence of a leak, taking great care not to allow pneumocephalus. The drain should be kept in place for up to 10 days; if the leak has not stopped at that point, repeat surgery with packing of the sphenoid sinus or other site of leakage should be carried out.
The second most common complication is prolonged diabetes insipidus, which presumably results from stalk injury; this should be avoided by careful curet use.
Intrasellar haemorrhage occurs in 1 percent or fewer of pituitary adenoma resections. It can be minimized by meticulous haemostasis, which may involve use of the bipolar cautery, judicious use of Surgicel, and patience in waiting for spontaneous haemostasis.
Loss of pituitary function can be avoided by carefully identifying the normal anterior pituitary during the curetting and avoiding removing it. Loss of posterior lobe function can similarly be avoided by identifying this lobe accurately and avoiding injury to it.
The most serious potential complication is injury to the carotid artery, which occurs in 1 percent or fewer patients. One should know from the MR scans where the carotid artery is and avoid curetting or manipulating it. Any haemorrhage should be immediately stopped by pressure and packing, and postoperative angiography should be done to detect false aneurysm formation.
Delayed Complications There are several delayed complications that may follow surgery for these tumors. Diabetes insipidus may occur after resection of medium-sized tumors in patients who had good posterior lobe function preoperatively. It is not a major problem because of the availability of desmopressin acetate (DDAVP), but it should be recognized early. More insidious is a phenomenon of inappropriate vasopressin secretion that may follow surgery by 4 to 7 days. With this condition, a patient may appear in the emergency room 8 days after a procedure with nausea and vomiting and a sodium level of 125 mmol/litre or less. This sequela can best be avoided by monitoring serum electrolytes closely for the first 2 weeks.
Sinusitis may be a distressing problem, requiring antibiotics for 2 weeks or more.
Craniotomy is used for pituitary adenomas with supra-para-antesellar extension; when it is used, a right pterional approach is one of the options; when there is severe visual loss. the approach is through the side of the more impaired eye, if the tumour configuration allow this, however, in special situations approaching from the other side could be more effective. The patient's head is turned 45 degrees to the left. and the Mayfield head holder maintains position. An anterior curvilinear incision is used; a small frontal flap is removed with care to get anteriorly. The right frontal lobe is gently supported and, using an operating microscope. the tumour is approached anterior to the chiasm. posterior to it in the midline. or between the carotid artery and optic chiasm. A variety of curettes are used to remove tumour tissue; the stalk is preserved if possible.
Complications of craniotomy include seizures, impaired vision, frontal lobe infarction or oedema. and unilateral anosmia.
Postoperative radiation therapy in general use for nonfunctioning adenomas only if there is residual tumour that is demonstrably growing. This differs from our practice for functioning adenomas, in which irradiation is done if there is an endocrine abnormality. This has been an area where radiosurgery is particularly useful in our experience, and new techniques of radiosurgery or stereotactic radiotherapy will very likely become the modality of choice for these lesions. A combination of surgery plus radiation will provide 85 percent or higher tumour control over 20 years