Transsphenoidal pituitary surgery
Neoplasms of the hypophysis represent approximately 10% of all brain tumours, and transsphenoidal pituitary surgery accounts for as much as one-fifth of all intracranial operations performed for primary brain tumours. In current practice, most sellar tumours are approached via the endonasal endoscopic approach, the classic sublabial approach being indicated only in a minority of patients for whom endonasal exposure may prove inadequate.
Patients with pituitary disease present with specific anaesthetic challenges. Common concerns relate either to the systemic effects of secreting adenomas, such as acromegaly and Cushing’s disease – which will be discussed in detail – or the intracranial mass effect of large adenomas. Rapidly worsening visual impairment represents the main indication for emergency hypophysectomy and optic chiasm decompression.
Pituitary anatomy and physiology
The pituitary gland – or hypophysis – sits in the sella turcica (the Turkish saddle), a midline saddle-shaped depression in the sphenoid bone in the middle cranial fossa. T e hypophysis is enveloped by the dura mater lining the sella and is covered by an open dural fold (diaphragma sellae). Te hypophyseal stalk (infun-dibulum) runs through the opening of the diaphragma sellae, connecting the hypophysis and hypothalamus.
The pituitary gland is surrounded by a number of vital structures that may either be compressed by enlargement of the gland or damaged during surgical excision of pituitary tumours. T e optic chiasm sits directly above the sella, and macroadenomas can compress the optic axons originating from the medial retina and crossing at the chiasm, typically causing temporal (or bitemporal) hemianopia. Te cavernous sinuses, the internal carotid arteries, oculomotor nerve (III), trochlear nerve (IV), abducens nerve (VI) and the first two divisions of the trigeminal nerve (V) lie at both sides of the pituitary gland. Cranial nerve palsies (diplopia) are signs of lateral expansion of a pituitary tumour. Te hypothalamus and third ventricle lie above the sella. Compression of these structures by large tumours can lead to headache, hypothalamic abnormalities, hydrocephalus and raised intracranial pressure (ICP).
Systemic signs and symptoms associated with pituitary disease may also be related to its endocrine physiology. Te hypophysis is formed by two functionally distinct parts. Te anterior pituitary gland (or adenohypophysis) comprises 80% of the hypophysis and synthesizes six hormones: growth hormone (GH), adrenocorticotropic hormone (ACTH), prolactin (PRL), thyroid-stimulating hormone (TSH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Tese hormones are released from the anterior pituitary under the influence of hypothalamic releasing hormones (GH-releasing, gondatotropin-releasing, TSH-releasing and ACTH-releasing hormones) and inhibitory hormones (somatostatin or GH-inhibiting, and dopamine or PRL-inhibiting). Hypothalamic hormones are transported to the anterior pituitary by way of a special capillary system running in the hypophyseal stalk, the hypothalamic-hypophyseal portal system.
Te posterior pituitary (neurohypophysis) is not a gland but a nervous structure with an endocrine function, being an intrasellar expansion of the hypothalamus capable of releasing hormones into the systemic circulation. Te neurohypophysis contains hypothalamic axons originating from the supraoptic and paraventricular nuclei of the hypothalamus, and specialized glial cells called pituicytes. Tese hypothalamic nuclei synthesize oxytocin and antidiuretic hormone, which are then secreted into the capillaries of the posterior hypophyseal circulation.
Pituitary disease
Pathology
The vast majority of intrasellar masses are pituitary adenomas, which can be locally invasive but do not metastasize. Pituitary adenomas are extremely common: their estimated prevalence in the overall population ranges from 14.4% in autopsy studies to 22.5% in radiological studies. Primary pituitary carcinomas and secondary metastases, the latter originating mostly from primary carcinoma of the lung, are rare. Other relatively uncommon pituitary masses include tumours of ‘epithelial remnants’ (craniopharyngiomas, chordomas), benign lesions (meningiomas, hamartomas, chondromas) and granulomatous/ inflammatory lesions (sarcoidosis, tuberculomas, abscesses).
Pituitary adenomas are classified according to their size, immunohistochemistry and functional status (Fig. 17.1). According to their endocrine profile, adenomas are classified as ‘functioning’ (hormone-secreting) adenomas, or ‘non-functioning’ (non-secreting) adenomas. Frequent among secreting adenomas are GH-secreting adenomas and PRL-secreting adenomas. ACTH-, TSH-, FSH- and LH-secreting adenomas are relatively rare. So-called ‘non-functioning’ adenomas account for approximately one-third of all pituitary adenomas. However, although ‘non-functioning’ adenomas are devoid of clinically significant systemic endocrine ef ects, the majority stain positively by immunohistochemically for gonadotropin subunits (P-LH, P-FSH or a-subunit).
Fig. 17.1. Histology of surgically excised pituitary tumours-relative prevalence. NFA, non-functioning adenomas; GH, somatotrope adenomas; PRL, prolactinomas; ACTH, Cushing’s disease; others, TSH-secreting and gonadotropin-secreting adenomas.
Adenomas can be further classified according to their size. Tumours >1 cm are classified as ‘macroad-enomas’, while tumours <1 cm are classified as ‘micro-adenomas’. With the exception of ACTH-secreting adenomas, which tend to be diagnosed early due to signs of hypercortisolism (Cushing’s disease), the majority of all other adenomas – including secreting adenomas – tend to be diagnosed when their size exceeds 1 cm and are therefore classified as macroad-enomas at the time of diagnosis. Non-functioning adenomas are, by definition, not associated with signs or symptoms of hormone excess, and they present with features relating to their mass effect.
With an increasing number of patients undergoing head CT or MRI for unrelated disorders (predominantly headache), more pituitary masses are being diagnosed in otherwise asymptomatic patients. While the incidental finding of a macroadenoma is a relatively rare occurrence, the prevalence of microadenomas in young and fit patients is surprisingly high. Te prevalence of pituitary abnormalities detected by MRI in healthy volunteers varies from 0.3% for macroadenomas to 10% for micro-adenom as. Tese have a small risk of further enlargement, and surgery is not indicated in such cases. Non-secreting microadenomas are managed with a ‘watchful wait’ approach, repeating an MRI scan at 1 year. If the adenoma is not growing and is not hormonally active, no further imaging or laboratory testing is required, unless indicated by a worsening clinical picture.
Pituitary hyperplasia is also a common cause of pituitary enlargement. It is caused by excess secretion of hypophyseal releasing hormones stimulating pituitary growth and activity, and must be distinguished from pituitary adenoma. Pituitary hyperplasia can be observed in cases of primary hypothyroidism leading to reflex TSH-releasing hormone hyperproduc-tion, or acromegaly secondary to ectopic (carcinoid) GH-releasing hormone (GHRH) secretion.
Worthy of mention here is the so-called empty sella syndrome, a rare condition that is characterized by a downward prolapse of the arachnoid through the diaphragm into the sella. Although there is no tumour, the sella is progressively enlarged by cerebrospinal fluid (CSF) pressure and the hypophysis is compressed against the posterior wall of the sella, causing panhypopituitarism.
Acromegaly
Acromegaly is a complex clinical condition caused by an excessive production of GH and characterized by an acquired progressive somatic disfigurement involving the face and extremities but also involving many other organs. he term (from the Greek akros meaning ‘extremities’ and megas meaning ‘big’) was introduced by Pierre Marie, a French neurologist who published the first description of the disease and its pathology in 1886. he term ‘gigantism’ refers to excessive production of GH beginning prior to pubertal closure of the epiphyseal plates.
The insidious progression of the disease typically leads to a late presentation and diagnosis. Acromegalic patients presenting for hypophysectomy are usually in their 40 s and are presumed to have suffered from the disease for at least 4 years at the time of diagnosis. Most GH-secreting adenomas are therefore macroad-enomas, and patients have well-established anatomical and physiological changes at the time of surgery. he clinical diagnosis is confirmed by MRI and biochemical tests. Diagnostic laboratory findings include increased serum GH concentrations that are not suppressed following an oral glucose load (oral glucose tolerance test) and an increased serum concentration of the major GH-dependent growth factor, insulinlike growth factor 1 (IGF-1). he excess GH originates from a monoclonal pituitary adenoma in >95% of acromegaly cases. In the case of a negative head MRI, other rare causes of acromegaly not related to pituitary adenomas include carcinoid tumours of the pancreas or lung-secreting GHRH, or genetic syndromes such as McCune-Albright syndrome.
Physical and facial appearances of acromegaly are characteristic. Hands and feet are broadened. Fingers are stubby. he nose is widened and thickened, the cheekbones are prominent, the forehead is bulging and the lips are bulky. Craniofacial changes include man-dibular and maxillary overgrowth, prognathism, jaw thickening, teeth malocclusion and nasal bone hypertrophy. Systemic features of acromegaly include diffuse skin thickening and hyperhydrosis, periosteal bone growth and skeletal deformation resulting in rheum-atological complications such as multiple peripheral arthropathy, spinal changes leading to significant kyphoscoliosis, and neuropathies, with carpal tunnel syndrome reported in up to 75% of cases. Prognatism, macroglossia, hypertrophy of the uvula and epiglottis, and calcinosis of the larynx may cause difficult laryngoscopy. Unanticipated difficulty with airway management is more than three times more common in acromegalic patients (9.1%) than in patients with non-functioning pituitary tumours. Hoarseness should alert the physician to the possibility of laryngeal stenosis or recurrent laryngeal nerve injury. Cardiovascular manifestations (hypertension, myocardial hypertrophy), metabolic complications (diabetes in up to 56% of cases) and respiratory complications (sleep apnoea reported in up to 80% of cases) are also common. Overall, acromegaly is associated with increased mortality: 60% of patients die from cardiovascular disease, 25% from respiratory complications and 15% from cancer. Cardiac involvement is a GH-specific feature of acromegaly that occurs even in the absence of hypertension. It is initially asymptomatic and usually consists of hyperkinetic, concentric ventricular hypertrophy. Clinical symptoms such as dyspnoea and poor exercise tolerance, arrhythmias and/or conduction disorders (ventricular premature complexes are common) should be actively investigated as they may indicate congestive heart failure, especially in patients with other risk factors such as diabetes and sleep apnoea. Valve disorders can also contribute to the onset or aggravation of heart failure in patients with acromegaly. In contrast to myocardial hypertrophy, valve disorders persist even after effective treatment of acromegaly. Hypertension is due to endothelial dysfunction and chronic hypervolaemia, with a plasma volume 10-40% above normal due to increased renal sodium reabsorp-tion at the distal tubule level. Sleep apnoea syndrome is also likely to contribute to the pathogenesis of hypertension. Respiratory complications of acromegaly are common, with sleep apnoea affecting the majority of patients. Hypercollapsibility of the pharyngeal walls and macroglossia cause obstructive apnoea, but up to one-third of patients are also reported to have central apnoea. Snoring, daytime sleepiness, morning fatigue and headache are common warning signs that should be documented and kept in consideration. Although subclinical hypoxaemia is sometimes present, no ven-tilation-perfusion mismatch has been demonstrated in acromegaly. A minority of patients will require prolonged nocturnal positive pressure ventilation for persistent sleep apnoea, despite successful treatment of acromegaly. Metabolic complications are related to insulin resistance, hyperinsulinism and increased blood glucose levels. Diabetes and glucose intolerance are diagnosed in up to 50% of cases.
Endoscopic transsphenoidal excision of pituitary adenoma is the first-line treatment for acromeg-aly. However, in one-third of cases, surgery fails to reduce GH and IGF-1 concentrations to normal levels. Negative prognostic factors include large tumour size and high pre-operative GH concentrations. When surgery fails to achieve good disease control, or when surgery is contraindicated, alternative options include stereotactic radiotherapy and/or pharmacological treatments, including somatostatin analogues (octreotide, lanreotide), dopamine agonists (cabergoline, bromocriptine), and GH-receptor antagonists (pegvi-somant). Repeated transsphenoidal surgery is also considered if medical treatment is poorly tolerated or ineffective.
Cushing’s disease
Cushing’s disease is caused by an ACTH-secreting (corticotropic) pituitary adenoma, first described by Harvey Cushing in 1912. As ACTH controls the release of cortisol from the adrenal cortex, non-feedback-loop-controlled ACTH secretion by pituitary tumours causes excess cortisol secretion by the adrenal gland. Hypercortisolism leads in turn to central obesity, muscle wasting, skin atrophy (purple striae), diabetes, hypertension, cardiomyopathy, amenorrhoea, decreased libido, osteoporosis and psychiatric abnormalities. Tis broad collection of signs, symptoms and metabolic changes related to hypercor-tisolism is summarized in the definition of Cushing’s syndrome. Although in the majority of cases Cushing’s syndrome is caused by an ACTH-secreting pituitary adenoma (true Cushing’s disease), other causes of Cushing’s syndrome include ectopic ACTH production (lung carcinoids, pancreatic islet tumours), primary excess cortisol production from adrenal tumours and iatrogenic glucocorticoid excess. Nelson’s syndrome refers to the aggressive and often invasive growth of an ACTH-secreting pituitary tumour following bilateral adrenalectomy in patients with Cushing’s disease. Te risk of patients with Cushing’s disease developing Nelson’s syndrome following bilateral adrenalectomy is high, ranging from 15 to 46%. Cushing’s disease represents approximately 8% of pituitary adenomas presenting for surgical excision. As corticotropic adenomas tend to cause early signs and symptoms, ACTH-secreting tumours are the only pituitary tumours that are mostly diagnosed as microadenomas.
The patient’s appearance is one of generalized obesity of the face, trunk and abdomen. A short and thick neck with a characteristic dorsocervical fat pad, and macroglossia are common predictors of difficult intubation. Although patients with Cushing’s disease are statistically no more difficult to intubate than patients with non-functioning tumours, it must be pointed out that, when this is the case, there is a risk of a ‘can’t intub-ate, can’t oxygenate’ emergency, as Cushing’s syndrome is also associated with multiple predictors of difficulty for bag-mask ventilation (obesity, obstructive sleep apnoea, decreased chest wall compliance). Airway access through the cricothyroid membrane can be difficult or impossible in patients with obesity of the neck.
Cushing’s disease carries a fourfold risk of mortality, largely related to obesity, diabetes, hypertension and cardiovascular disease. Other significant morbidities in Cushing disease include hyperlipidaemia, coagu-lopathy, osteoporosis, depression, anxiety and cognitive impairment. Overt diabetes mellitus is diagnosed in one-third of all patients with Cushing’s disease. As hyperglycaemia can aggravate ischaemic injury of the brain and spinal cord, blood glucose levels in excess of 180 mgdl-1 (10 mmol l-1) should be treated with intravenous insulin perioperatively in all cases. Te maj ority of patients with Cushing’s disease have systemic hypertension, with a presenting diastolic blood pressure >130 mmHg in 10% of patients. Increased endogenous corticosteroids can cause hypertension by m any different mechanisms, including increased cardiac output and increased hepatic production of angiotensinogen, which in turn activate the renin-angiotensin system causing sodium retention and plasma volume expansion. Glucocorticoids also reduce the synthesis ofvaso-dilatory prostaglandins and increase the expression of angiotensinogen II, leading to increased sensitivity to endogenous vasoconstrictors such as angiotensin II, epinephrine and norepinephrine. Tis is relevant to anaesthetic management, as sensitivity to exogenous catecholamines may also be exaggerated. Left ventricular hypertrophy is often detected on 12-lead ECG and echocardiography. Echocardiography can reveal disproportionate hypertrophy of the intraventricular septum, with diastolic dysfunction in at least 40% of patients. Exercise tolerance is often limited by obesity, and congestive cardiac failure is not uncommon. As in the case of cardiomyopathy related to acromeg-aly, ECG and echocardiographic abnormalities often regress after curative adenomectomy. Obstructive sleep apnoea is common among patients with Cushing’s disease. Polysomnographic studies indicate that one-third of patients with Cushing’s disease have mild sleep apnoea, and about one-fifth of patients have severe sleep apnoea, suggesting higher risk of airway obstruction in the perioperative period. Sedative analgesics should be used with caution, and perioperative non-invasive positive-pressure ventilation m ay be indicated in selected cases. Patients suffering from Cushing’s disease tend to have atrophic skin, and veins are often fragile and prone to bruising. In morbidly obese patients, venous cannulation can be extremely difficult. Such patients should be forewarned of the option of inhalational induction of anaesthesia. Although myopathy is common among patients with Cushing’s disease, there is no specific contraindication or abnormal response to succinylcholine or non-depolarizing neuromuscu-lar blockers. Osteoporosis is common, and particular care is needed when positioning the patient.
Effective surgical treatment restores normal corti-sol levels and results in survival rates similar to those of the general population. Transsphenoidal selective ade-nomectomy is the treatment of choice, with partial or total hypophysectomy being surgical alternatives if the adenoma cannot be identified. Remission rates vary between 69 and 98%, with an acute surgical mortality rate of <2%. After failed transsphenoidal surgery for Cushing’s disease, treatment options include repeated transsphenoidal surgery, radiotherapy, pharmacological therapy and bilateral adrenalectomies. Te last option carries a significant risk of Nelson’s syndrome. Selective adenomectomy and partial or total hypophysectomy have similar long-term remission rates. However, with increased removal of pituitary gland tissue, there is an increased rate of anterior and posterior pituitary failure.
Thyroid-stimulating hormone-producing adenomas
Thyrotropic adenomas represent <3% of all pituitary tumours and are a rare cause of hyperthyroidism. Te clinical features of patients with TSH-producing adenomas are the same as those of patients with primary hyperthyroidism. Goitre is common, and symptoms include palpitations, tremor, weight loss, difficulty sleeping, heat intolerance and sweating. Patients are often initially misdiagnosed with more common causes of hyperthyroidism, such as Graves’ disease. As a consequence, thyrotropic adenomas often remain unidentified and are allowed to grow for years, and tend to be large upon diagnosis. As for other hor-monally active pituitary adenomas, medical therapy can help control symptoms but is rarely curative, and transsphenoidal hypophysectomy is the treatment of choice. Somatostatin analogues (octreotide) can suppress the production of TSH and reduce tumour size, while antithyroid medication (such as propylthiouracil 200-300 mg four times daily) reduce thyroid hormone secretion, controlling hyperthyroidism. If a P-blockade is started (propranolol 30-60 mg three times daily) to control tremors or palpitation, it should be continued perioperatively.
Prolactinomas
Although PRL-secreting adenomas are the most commonly diagnosed pituitary tumour, the condition responds well to medical treatment and only a minority of patients are candidates for surgery. Patients with a prolactinoma are no more difficult to intubate than patients with non-functioning tumours, and hyper-prolactinaemia does not have systemic ef ects that imply specific anaesthetic issues.
Prolactinomas are slow-growing adenomas and tend to remain stable in size for years. Symptoms are related to hyperprolactinaemia and suppressed gonado-tropin secretion leading to menstrual disturbances, vir-ilization and infertility in women, and gynaecomastia, loss of libido and oligospermia in men. Galactorrhoea is more evident and occurs mostly in women, so the diagnosis is made earlier, and PRL-secreting adenomas tend to be smaller at diagnosis in female patients.
Prolactin is secreted under the dominant inhibitory hypothalamic control of dopamine, and the vast majority of patients respond well to medical therapy with a dopamine agonist such as bromocriptine. However, medical treatment needs to be continued for life, and a minority of patients do not tolerate or do not respond to dopamine agonists. Transsphenoidal hypophysectomy is the second-line therapeutic option in such cases.
Craniopharyngiomas
Craniopharyngiomas were first described by Erdheim in 1904as ‘hypophysial duct tum ours’, but it was Cushing who later used the term ‘craniopharyngioma’ to define these benign tumours that develop along the pituitary stalk. Craniopharyngiomas originate from infundibular remnant nests of epithelium of Rathke’s pouch, an embryonic precursor of the anterior pituitary.
Craniopharyngiomas represent 5% of all primary central nervous system (CNS) tumours diagnosed in childhood. Tey often have suprasellar extension and may be cystic and/or calcified. Tese features are helpful in differentiating craniopharyngiomas from pituitary adenomas on neuroimaging. Craniopharyngiomas present with symptoms of pituitary stalk compression, visual disturbances and hypopituitarism.
Transsphenoidal excision of a craniopharyngioma presents specific perioperative issues, caused by its tight adherence to vascular and cerebral structures, which can make surgery difficult. Although radical excision provides the best long-term remission, aggressive surgery is associated with significant incidence of complications, including profuse haemorrhage, CSF leak and hypopituitarism. Stereotactic radiotherapy, in the form of radiosurgery or fractionated stereotactic radiotherapy, is currently used in patients after limited surgery and achieves excellent long-term tumour control with minimal side effects.
