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Neuroendocrine Tumors: Pathophysiology

I. Anatomy

Intracranial mass. Many neuroendocrine tumors are microadenomas (<10 mm in size) and require routine induction and maintenance of anesthesia for their surgical extirpation. Some tumors are very large and require attention to blood pressure (BP), airway dynamics, and other factors affecting intracranial pressure (ICP) during induction of anesthesia, maintenance, and emergence.
Pituitary gland and stalk are very close to the optic chiasm, intracranial carotid arteries, cavernous sinuses, and cranial nerves.
Pituitary adenomas may be either intrasellar or extracranial and may extend laterally into the cavernous sinuses.
Cavernous sinus contains the intrasphenoid carotid artery and cranial nerves III, IV, V1, V2, and VI (Figure-1).
Magnetic resonance imaging (MRI) appearance and extension of the tumor are important for planning anesthetic management and neurophysiologic monitoring.
Pituitary tumors can extend out of the sella into the intracranial space and involve the optic chiasm and carotid arteries.

II. Endocrine physiology: anterior pituitary

The hypothalamus secretes hormone-releasing factor (RF), which is transported to the median eminence of the hypothalamus by axonal flow. The RF is then transported via the hypothalamo-hypophyseal portal system to the anterior pituitary. Hormones are secreted into the systemic circulation in response to a variety of stimuli. Target organs respond to stimuli and send negative feedback to the pituitary and the hypothalamus to turn off the secretion of RF and stop the release of the hormone. The incidence of asymptomatic microadenomas on autopsy is up to 27%. The peak age of occurrence is 40 years. Prolactinomas account for approximately 40% of all symptomatic microadenomas.
Anterior pituitary hormones (adrenocorticotropic hormone [ACTH], growth hormone [GH], prolactin [PRL], thyroid-stimulating hormone [TSH], luteinizing hormone [LH], melanocyte-stimulating hormone [MSH], and follicle-stimulating hormone [FSH]) may all be produced by microadenomas. ACTH, GH, and PRL are produced most commonly. All have inhibiting factors and RFs, and all can be accurately measured in the blood using radioimmunoassay techniques.

Figure-1. Coronal section through pituitary gland demonstrating perisellar structures and sphenoid sinuses. Cranial nerves: ocular nerve (III), trochlear nerve (IV), trigeminal nerve (V), abducens nerve (VI).

Cushing's disease is caused by an ACTH-secreting pituitary tumor.
Cushing's syndrome occurs when there is an ACTH-dependent (ACTH administration, ectopic ACTH syndrome) or ACTH-independent (adrenal adenoma, carcinoma, or exogenous cortisol administration) excess secretion of cortisol.
Ectopic ACTH is associated with a primary oat cell carcinoma of the lung.
a. The tumor produces ACTH- and corticotropin-releasing factor (CRF)-like peptides.
b. Plasma cortisol is >50 mcg/dL.
c. Explosive hypercortisolism may occur with the following:
(1) Hypertension
(2) Glucose intolerance
(3) Hyperaldosteronism (hypokalemic alkalosis)
(4) Marked hyperpigmentation
Cushing's disease
1. Truncal obesity, posterior cervical fat pads, osteoporosis, and moon facies are characteristics.
2. Hypertension and glucose intolerance can occur.
3. Adrenal hyperplasia. In the past, many patients had bilateral adrenalectomy to treat what was thought to be a primary adrenal condition (Nelson's syndrome). These patients may then come for surgery later to remove what was actually a primary pituitary tumor.
4. CRF is stimulated by acetylcholine and serotonin and inhibited by norepinephrine.
5. Cortisol secretion is 16 mcg/day, 75% of which is bound to transcortin protein.
6. Normal diurnal variation is 4 am to 8 am: 25 mcg/dL; 4 pm to 8 pm: <10 mcg/dL. Normal diurnal variation increases with stress and pregnancy.
7. Diagnosis is based on loss of diurnal variation, increased ACTH, and probable MRI evidence of sellar adenoma.
Acromegaly, a GH-producing tumor, leads to the following:
Signs and symptoms
1. Bony and soft tissue enlargement (frontal bossing, prognathism, increased ring, glove, and shoe size)
2. Hypertension
3. Glucose intolerance
4. Visual loss if tumor is large and involves chiasm
5. Hoarseness (soft tissue stretching of cranial nerve X)
6. Dyspnea (narrow glottis from soft tissue overgrowth)
7. Cardiomyopathy from lymphocytic infiltration, a common cause of death, if untreated
8. Carpal tunnel syndrome from soft tissue overgrowth
9. Lumbar spinal stenosis and cervical compression from bony overgrowth
Hypoglycemia is the most potent stimulus to the secretion of GH. Somatostatin inhibits the release of GH.
Diagnosis includes random blood GH of >10 ng/mL (2 to 5 ng/mL normally) and elevation of somatomedin C (produced in the liver in response to GH stimulation so that high levels occur only with acromegaly).
Acromegaly and the airway
1. Hypertrophy of the mandible, nasal turbinates, soft palate, tonsils, epiglottis, arytenoids, tongue, lips, and nose may occur.
2. The glottis might be narrow.
3. Vocal cord paralysis can be present from soft tissue overgrowth.
4. Most often routine intubation techniques are successful, but the ready availability of extra-long blades, smaller endotracheal tubes, laryngeal masks, and fiberoptic intubation equipment is essential.
5. Anticipate difficult mask fit and potential postextubation stridor.
6. Patients frequently have a consultation with an otolaryngologist before an operation. A report of the indirect laryngoscopy performed by that consultant is obtained to facilitate anticipation of and preparation for airway difficulty.
PRL-secreting tumors may be larger in men than women because women tend to seek medical attention earlier because of infertility. Other signs and symptoms include amenorrhea, galactorrhea, anovulation, decreased libido, gynecomastia, and osteoporosis.
PRL secretion is primarily regulated by dopamine, which functions as an inhibitory factor. PRL is released by thyrotropin-releasing hormone, serotonin, and the stress of anesthesia and surgery. The secretion of PRL is increased by pituitary stalk section (which interrupts dopaminergic fibers), serotonin, phenothiazines, alpha-methyldopa, and menopause.
Normal PRL is 15 to 25 ng/mL.
Diagnosis. PRL >25 ng/mL is present. Eighty percent of patients whose PRL exceeds 200 ng/mL have adenomas even if their presence is not demonstrated neuroradiologically. When PRL exceeds 2,000 ng/mL, invasion of the cavernous sinus is likely. This may warrant additional intravenous access and monitoring with electroencephalogram (EEG) and evoked potentials.
Amenorrhea. PRL >30 ng/mL is present.
Loss of libido. PRL of >300 ng/mL is present.
Menopause. PRL is increased, and estrogen is decreased.
Nonfunctioning pituitary tumors include adenomas, craniopharyngiomas, meningiomas, and aneurysms. These tend to be large and involve perisellar structures.

III. Endocrine physiology: posterior pituitary

Antidiuretic hormone (ADH)
Produced in the supraoptic and paraventricular nuclei of the hypothalamus
Stored in the median eminence of the hypothalamus
Transported with a carrier protein, neurophysin, along the hypothalamic hypophyseal tract to the posterior pituitary
Released into the systemic circulation after appropriate stimulus: increased serum osmolality, pain, opiates, and decreased circulating blood volume, which causes the greatest ADH release and concurrent vasoconstriction
Secretion inhibited by decreased serum osmolality, alcohol ingestion, increased blood volume, phenytoin
ADH attaches to an adenyl cyclase receptor on the medullary interstitial surface of the renal collecting duct epithelium. This causes an increase in cyclic adenosine monophosphate, which increases the permeability of the collecting ducts to water, and water is reabsorbed. In the absence of ADH, pure water is lost.
Diabetes insipidus (DI) can be present preoperatively, may also occur intraoperatively, and may be temporary or permanent in the postoperative period.
Signs and symptoms include polyuria (3 to 15 L/day), polydipsia, serum hyperosmolality (>320 mosmol/mL), dilute urine (specific gravity 1.001 to 1.005, osmolality 50 to 150 mosmol/mL), and urine/serum osmolality <1.
Administration of salt-containing solutions causes the patient to develop severe hypernatremia and hyperosmolality. Oral intake is initiated as soon as possible.
Administration of glucose-containing solutions causes the patient to develop hyperglycemia and osmotic diuresis. Oral intake is initiated as soon as possible.
Total body water deficit calculation in a 70-kg patient:
1. Normal serum sodium, (Na) = 140 mEq/L
2. Total body water = 60%, of total body weight = 42 L
3. Normal body sodium = 42 L 140 mEq/L = 5,880 mEq Na
4. Patient's Na = 160 mEq/L
5. Patient's body water = 5,880 mEq/160 mEq/L = 36.7 L
6. Water deficit = 42 L - 36.7 L = 5.3 L
Drug therapy indicated in patients who cannot drink the necessary volume, are not taking anything by mouth, or are anesthetized includes:
a. 1-Deamino-8-bd-arginine vasopressin (DDAVP), 10 to 40 mcg intranasally. This daily dose may be divided into 2 or 3 doses beginning with 10 mcg at bedtime and increased by 2.5 mcg/day up to a total dose of 40 mcg/day. DDAVP, 0.01 to 0.03 ng/kg every 12 hours, may also be given intravenously.
b. Lysine vasopressin, 5 to 10 units administered subcutaneously or intramuscularly 2, 3, or 4 times a day, or 0.5 to 2 microunits/kg/hour administered intravenously (i.v.).
c. Other drugs include vasopressin tannate-in-oil, which is used less commonly. Its effect lasts up to 36 hours after a single dose.
d. Overdose of drugs leads to an iatrogenic syndrome of inappropriate antidiuretic hormone (SIADH) secretion.

IV. Pituitary tumors

Signs and symptoms
Headaches are bitemporal or bifrontal.
Bitemporal hemianopsia is classic but its presence depends on the relationship of the pituitary tumor to the optic chiasm and nerves.
Ophthalmoplegia involving cranial nerves III, IV, and VI and facial paralysis involving cranial nerve VII occur. Corneal anesthesia involving cranial nerve V is related to invasion or compression of the cavernous sinus.
Seizures may be related to the extension of the tumor into the temporal lobe but are rare.
Hypothalamic dysfunction includes abnormal temperature regulation, thirst, and appetite changes, all of which are rare.
DI may occur.
Endocrinopathies. Syndrome of multiple endocrine neoplasia may include parathyroid dysfunction with hypercalcemia and TSH-, ACTH-, LH-, and FSH-producing adenomas.
Diagnosis. MRI is the gold standard for diagnosing micro-versus macroadenoma (T1-hypointensity; T2-hyperintensity) but is poor for visualizing bony changes and identifying cavernous sinus invasion. Angiography facilitates hormone sampling from the petrosal vein.
Panhypopituitarism is a clinical diagnosis confirmed by assaying specific hormones.
Most patients who have microadenomas are clinically normal and do not demonstrate any signs of panhypopituitarism.
Nonetheless, in some institutions, it is customary to administer hydrocortisone, 50 to 100 mg i.v., before induction of anesthesia and then 10 mg/hour by infusion until the patient's postoperative course indicates that the drug is no longer necessary.
Thyroid replacement may be administered orally as levothyroxine sodium (Synthroid) and very rarely as an intravenous infusion.
DI is treated with DDAVP and appropriate fluids. If panhypopituitarism has been diagnosed preoperatively, the patient may already be receiving replacement steroids and DDAVP.
Intraoperative management
Monitoring is appropriate for the patient's physiologic status.
1. Consider either EEG or evoked potential monitoring if there is marked involvement of the cavernous sinus or perisellar area.
2. In some institutions, pituitary operations are performed in a head-elevated position. Venous air embolism (VAE) could occur, so end-tidal gas monitoring is recommended. If, VAE occurs, the head can be lowered rapidly to treat the air embolism. The need for central venous access is determined by the size and location of the tumor and/or by the patient's medical condition. However, careful monitoring of fluid intake and output is indicated in every patient.
3. Visual evoked responses are not monitored in most institutions and are not indicated for patients who have microadenomas, but it is desirable when the tumor reach giant sizes.
Anesthetic technique is selected to permit early postoperative assessment of vision, ocular movements, pupil size, and motor strength.
Antibiotic prophylaxis is typically cefazolin, 1 g i.v. every 3 to 4 hours.
Topical cocaine 4% and injected lidocaine 1% with epinephrine; if both are used, severe hypertension might occur from the unopposed alpha sympathetic effect.
Valsalva maneuvers advance the pituitary gland toward the surgeon to facilitate excision of the tumor and examination for trans-sellar cerebrospinal fluid (CSF) leak.
Avoid hyperventilation, insertion of nasogastric tubes, incentive spirometry, and the use of drinking straws. Hypoventilation (Paco2 42 mm Hg, ICP up to 20 mm Hg) is successful in producing the descent of the suprasellar portion of the tumor.
Postoperative management
Careful fluid and electrolyte management and treatment of DI, SIADH, and cerebral salt wasting are necessary.
Steroid maintenance and tapering. Patients who have Cushing's disease may have prolonged adrenal insufficiency and require steroid replacement for several months.
Acromegalics and patients with Cushing's disease have excess body water and will diurese postoperatively.
Patients who have had previous adrenalectomies (Nelson's syndrome) require mineralocorticoid replacement such as fludrocortisone acetate (Florinef), 0.1 to 0.2 mg/day by mouth.
Deep vein thrombosis and pulmonary emboli are not uncommon. Prophylaxis is recommended with heparin, intermittently inflating antithromboembolism stockings, and early mobilization.
Lumbar drains may be used postoperatively to treat CSF leaks.

V. Pituitary apoplexy

This syndrome is related to the sudden enlargement of a pituitary tumor because of hemorrhage or necrosis.
Symptoms and signs include acute loss of consciousness, hypertension, meningismus, eye pain, blindness, ophthalmoplegia, panhypopituitarism. It is important to differentiate this condition from subarachnoid hemorrhage from the rupture of an intracranial aneurysm.
Diagnosis is made on clinical grounds and with radiologic evidence of a pituitary tumor.
Treatment is urgent: surgical decompression of the optic system, systemic steroid replacement, and other hormone replacement as necessary. Some recommend bromocriptine therapy in lieu of surgery.

VI. Treatment of pituitary tumors

Radiation therapy is rarely used now because of the high incidence of panhypopituitarism and the long lag time for clinical effect, but it is still showing effective results with recurrence.
Medical therapy
  ACTH (Cushing's disease). Because there is no effective medical therapy, operative removal is recommended.
GH (acromegaly). Octreotide, a somatostatin inhibitor, is an expensive drug ($7,800 annually) that requires multiple daily subcutaneous injections. Octreotide reduces headaches and improves cardiomyopathy and can be used to treat patients in whom surgical results have been less than optimal. However, operative removal is preferred.
PRL. Bromocriptine or similar drugs such as pergolide are the first-line treatment.
1. They reduce tumor size and PRL levels.
2. They restore fertility. The risks of pregnancy in the presence of a pituitary tumor include its enlargement during pregnancy, which may necessitate operative removal. Perhaps tumor resection should precede pregnancy.
3. If patients are intolerant of the drug's side effects (nausea, dizziness, orthostatic hypotension), surgery is indicated.
4. Medical therapy must be continued long term to indefinitely when surgery is not performed.
Surgical therapy
Transsphenoidal: Approach to the floor of the sella is midline, transnasal, transsphenoidal.
1. Advantages include less damage to frontal lobes and olfactory apparatus, no external scar, direct visualization of microadenomas, minimal damage to normal pituitary, lower incidence of temporary and (rarely) permanent DI, less blood loss, and shorter hospitalization. Endoscopic transseptal approach to the sphenoid sinus has been found to be easy, time saving, and without complications.
2. Disadvantages include the potential for CSF leak and meningitis, lack of direct visualization of the optic apparatus, inaccessibility of large tumors, and blood loss that is more difficult to control. Bleeding may require packing the cavernous sinus with resultant compression of the cranial nerves and carotid artery, which could lead to contralateral neurologic deficit.
Transfrontal: bifrontal or unilateral craniotomy
1. Advantages include the ability to access suprasellar tumor extension and visualize optic system and other perisellar structures.
2. Disadvantages are higher morbidity than with transsphenoidal, increased likelihood of temporary and permanent DI, possible optic system and vascular injury, cerebral edema, and longer hospitalization.


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