In case of visual symptoms or disturbances of hormonal function, an adenoma of the pituitary gland may be present, which must be considered and clarified endocrinologically and by means of MRI of the skull or sella region. These tumors account for approximately 10-15% of primary brain tumors and are the most common pituitary disease in adults. Except for prolactin-producing adenomas, which are usually treated with dopamine agonists, surgical extirpation through a transnasal transphenoidal approach is the treatment of choice. Radiotherapeutic procedures are most often used adjuvantly or for recurrences.
Autopsy studies show pituitary tumor prevalence rates as high as 25%, indirectly underscoring the problem of potentially incidentally discovered pituitary findings. It is estimated that about one in 10,000 people are diagnosed with a pituitary adenoma each year, slightly more often in women than in men. They usually occur in the third and fourth decades of life, but can be diagnosed well into old age. Functional classification distinguishes hormone-active and hormone-inactive pituitary adenomas, and morphologic classification distinguishes microadenomas (≤10 mm) from macroadenomas (>10 mm).
Clinical presentation
Prolactinomas are the most commonly diagnosed, accounting for approximately 40-60%. Clinically they become noticeable by amenorrhea, galactorrhea or reduction of libido and potency. Men are often diagnosed later than women. Children are more likely to present with headache, primary amenorrhea, and growth failure. Laboratory chemistry shows that the prolactin level in these cases is several times above the norm. However, hyperprolactinemia (usually max. two to three times higher than the upper limit) can also occur due to compression of the pituitary stalk by a hormone-inactive adenoma (concomitant hyperprolactinemia or “stalk effect”) or often have non-pituitary causes: Hepatic and renal insufficiency, hypothyroidism, drug-induced (e.g., dopamine antagonists, estrogens).
Endocrine inactive pituitary adenomas are the second most common. These are usually macroadenomas, which become symptomatic due to their space-occupying effect on the pituitary gland and adjacent structures. Often, gonadotropin expression can be detected in these adenomas by immunohistochemistry, but this is usually not clinically relevant (“silent secreters”). Headache, visual field deficits (classic bitemporal hemianopsia), and adynamia due to pituitary insufficiency are the most common symptoms when a hormone-inactive adenoma is diagnosed. Large tumors break through the diaphragma sellae and may also lead to obstruction of the foramen Monroi and this in turn to hydrocephalus. Infiltration of the cavernous sinus may also cause cranial nerve deficits such as double vision or ptosis, as well as facial pain (cavernous sinus syndrome). Invasion of the temporal lobe may result in partial-complex epileptic seizures and memory problems. Pituitary apoplexy (Fig. 1) is usually an urgent surgical indication and is typically symptomatic by headache and visual disturbances and possibly disturbances of consciousness (as a result of pituitary insufficiency and/or electrolyte disturbances). Posterior pituitary lobe failure with diabetes insipidus is relatively rare and presents more commonly with suprasellar and hypothalamic tumors.
About 30% of all hormone-active pituitary adenomas secrete GH (“growth hormone” = somatotropin), mostly macroadenomas. Clinically, they present with gigantism in adolescents and acromegaly in adults. Signs of acromegaly include enlargement of the acra, swelling of the soft tissues, hyperhydrosis, macroglossia, prognathism, retroorbital pressure pain, carpal tunnel syndrome, and the development of a metabolic syndrome with diabetes and arterial hypertension. Other, non-pituitary tumors may also secrete GH or GHRH, leading to acromegaly. Since GH is secreted in a pulsatile manner, the diagnostic practice is to determine IGF1 (somatomedin). Repetitive determination of GH after ingestion of oral glucose (oral glucose tolerance test) confirms the diagnosis if suppression of GH cannot be achieved.
ACTH-secreting pituitary adenomas account for 15-25% of all hormone-responsive tumors. Approximately 80% of all Cushing’s syndromes are ACTH dependent (Cushing’s disease), with 85% of these cases involving a pituitary microadenoma (whereas approximately 15% involve an ectopic ACTH-producing tumor). Clinical symptoms include weight gain, truncal obesity, buffalo neck, acne, striae distensae, hirsutism, osteoporosis, hypertension, diabetes mellitus, sexual dysfunction, and depression. Laboratory confirmation of diagnosis can become very complex. Serum and 24-h urine cortisol determination and functional suppression tests (dexamethasone, CRH) are necessary. Rarely, when a microadenoma cannot be reliably visualized on MRI, ACTH measurement by superselective catheterization at the inferior petrosal sinus is needed. We do a catheterization even if a microadenoma is shown with certainty, since an incisional adenoma can still be present in about 10% of cases.
Rarely, a pituitary space deficit, which is due to hypertrophy, is seen in excess ACTH production after total adrenalectomy (for treatment of Cushing’s syndrome of extrahypophyseal cause). This complication is known as Nelson’s syndrome and is due to the lack of negative cortisol feedback.
Gonadotropin-producing adenomas can lead to pubertas precox or primary amenorrhea in children. However, these tumors are very rare as are TSH-producing adenomas.
Preoperative clarification
Preoperatively, a differentiated endocrinological clarification must be performed. If necessary, hormones must be substituted preoperatively. MRI of the sella region is the imaging modality of choice. T1 weighting in all three planes with and without contrast should be included. If a hormone-active microadenoma is suspected but the adenoma cannot be seen on primary MRI, it is advisable to decrease the contrast dose or to run dynamic MR imaging after contrast injection. A T2 sequence and MR angio are also helpful. Clear identification of the sella-adjacent structures (cavernous sinus, chiasm, vessels) is of enormous importance. A computed tomography scan is also often helpful, as the bony structures of the nasal cavity and sphenoid sinus can be seen more clearly. It is advisable to have a 3D dataset made from a sectional image so that neuronavigation can be used. If suprasellar extension is present, an ophthalmologic evaluation by means of visual acuity and visual field determination must be performed preoperatively. Furthermore, the general condition of the patient should of course be assessed from an anesthesiological point of view.
Therapy
If hypopituitarism, hormone secretion, visual field deficits, or documented tumor growth exist, treatment of the pituitary adenoma is indicated. If pituitary adenomas are discovered by chance during an MRI examination, as so-called incidentalomas, they are further clarified endocrinologically. If they are hormone inactive and there is no space-occupying effect, they can be further monitored by MRI examinations, e.g., after one, two, and after five years if stationary. Depending on the literature, tumor growth can be expected in about 10% of microadenomas and about 25% of macroadenomas.
Prolactinomas are primarily treated with bromocriptine or cabergoline. The goal is regular menstruation as well as a normal libido. Normalization of prolactin levels cannot be achieved with medication in every case. A discontinuation attempt can be made after two to five years, depending on tumor size. If drug therapy does not work or is not tolerated, there is an indication for surgery. This is a good treatment alternative, especially for microprolactinomas, because long-term remission can be achieved in >80% of cases. If cerebrospinal fluid (CSF) erysipelas occurs during tumor regression under drug therapy, there is also an indication for surgery.
Although equivalent drug therapies for GH-secreting adenomas have also been reported, surgery is the first-line therapy for these and for all other adenomas.
Surgical Technology
If the tumor is severely suprasellar and also asymmetrically located, it sometimes must be removed via craniotomy. However, about 90% of pituitary adenomas can be operated by a transnasal-transsphenoidal approach (Fig. 2). Depending on the anatomical conditions and surgeon preference, a mucosal incision is chosen in the nasal vestibule, sublabially or directly at the sphenoid to finally open the sphenoid cavity in the midline after insertion of a speculum. There, the mucosa is completely removed and the sella can be seen from the planum sphenoidale to the clivus. The aim is to resect the tumor as radically as possible, while sparing the normal pituitary gland. If the adenoma grows invasively into the cavernous sinus, portions of the tumor must usually be left in place. If cerebrospinal fluid flows intraoperatively, a watertight reconstruction of the sella floor is necessary.
More and more centers are using endoscopes for resection of pituitary adenomas, often in collaboration with ENT colleagues performing the approach. Visualization in the area of the sella is better with the endoscopic technique than with the microsurgical technique. However, no study has yet shown that the resection rate is higher with the endoscopic technique. Nasal morbidity, i.e., crusting, discharge, occurrence of sinusitis, is comparable with both techniques. The use of intraoperative MRI imaging has been reported by some studies to increase resection rates – but this technology has not yet become a generally accepted standard.
Ultimately, the size, extent, and invasiveness of the adenoma, as well as the surgeon’s experience, determine the resection rate and also the complication rate. The complication rate is relatively low (1-5%) for transphenoidal surgery. Meningitis and CSF fistulas are almost invariably well controlled. Like the mortality rate for the procedure, the probability of serious complications occurring, such as secondary bleeding leading to visual impairment or blindness, is well below one percent.
Postoperative control
Postoperatively, fluid balance, electrolytes, and body weight are monitored, and diabetes insipidus may occur transiently in the presence of ADH deficiency and/or hyponatremia may occur in the setting of ADH overproduction (SIADH). If pituitary insufficiency occurs postoperatively (in about 10% of cases), the appropriate hormones must be substituted. In the case of ACTH deficiency, the patient receives therapy with hydrocortisone, fixed or on demand depending on the cortisol level, as well as an emergency card (“stress prophylaxis”). Pathological workup should include immunohistochemical analysis as well as proliferation index. After discharge, patients undergo endocrinological and imaging follow-up according to regimen.
Radiotherapy
Here, stereotactic radiosurgery (single time, high dose, high precision irradiation = Stereotactic RadioSurgery, SRS) and fractionated radiotherapy (RT) are available options. Studies have evaluated SRS as a primary treatment option. Endocrine remission or growth control may also occur under this – but data on this vary widely. We recommend SRS as adjuvant treatment for symptomatic or progressive residual adenomas. The condition for the use of this strategy is the presence of a well-defined tumor with the smallest possible volume. For larger and/or less well demarcated lesions, fractionated radiotherapy is more recommended. After radiotherapy, gradual loss of anterior pituitary function is very common.
We thank Prof. Mjriam Christ-Crain, MD, for her critical review of the manuscript.
Further reading:
- Buchfelder M, Schlaffer S: Surgical treatment of pituitary tumors. Best Pract Res Clin Endocrinol Metab 2009 Oct; 23(5): 677-692.
- Molitch ME: Pituitary tumors: pituitary incidentalomas. Best Pract Res Clin Endocrinol Metab 2009 Oct; 23(5): 667-675.
- Jagannathan J, et al: Benign brain tumors: sellar/parasellar tumors. Neurol Clin 2007 Nov; 25(4): 1231-1249.
InFo ONCOLOGY & HEMATOLOGY 2015; 3(7): 14-17.
