Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.287664
Source of Support: None, Conflict of Interest: None
Keywords: Acromegaly, pituitary, transsphenoidal surgery, endoscopy, remissionKey Message: Transsphenoidal surgery is first-line treatment for the vast majority of patients with acromegaly. Contemporary outcomes with endoscopic transsphenoidal surgery are encouraging. Early diagnosis of the disease should improve outcomes. Management of acromegaly should be multi-disciplinary to optimize treatment strategies.
Acromegaly is a clinical syndrome secondary to unmitigated growth hormone (GH) hypersecretion, and is almost always secondary to a somatotroph pituitary tumor. Acromegaly profoundly impacts patient quality of life and overall survival, through its protean ramifications on cardiovascular health, sleep-disordered breathing, degenerative joint, lumbar spine and carpal tunnel disease and large bowel oncogenesis.,,,,,
A number of modern treatment options are available for patients with GH secreting pituitary adenomas; however the first line of therapy remains surgical removal of the tumor. This is because medical treatment of acromegaly is prohibitively both protracted and expensive, requiring life-long therapy with somatostatin analogues, dopamine agonists or GH receptor antagonists. Surgery provides the possibility of remission in a large proportion of patients, however tumor size and invasiveness are important determinants of surgical results, which are usually best in smaller, non-invasive tumors. Even in invasive tumors where gross total resection (GTR) is not possible, primary debulking may improve the response of residual disease to postoperative adjuvant therapy.,
The chief objectives of surgery in the management of patients with acromegaly may be summarized as follows:
After an initial detailed clinical assessment, including formal neuro-ophthalmological testing, a full pituitary hormonal panel must be obtained. This includes serum GH (basal and nadir post-suppression with oral glucose) and serum IGF-1 levels. Biochemical examination of the other hormonal axes is also important to detect complete or partial deficiency of other pituitary hormones including thyroid and cortisol. Delayed recovery from general anaesthesia, postoperative respiratory depression and haemostatic abnormalities are potential problems in patients with hypothyroidism, necessitating appropriate correction prior to surgery. Elevated prolactin levels in growth hormone secreting pituitary tumors are usually a consequence of the “stalk effect”, but may also infrequently be seen in patients with mixed somatomammotroph adenomas.
At our institution, we routinely obtain a preoperative echocardiogram before surgery in patients with acromegaly, to look for left ventricular hypertrophy, arrhythmias or cardiomyopathy, all of which can elevate the risk of a perioperative cardiac event. Other factors to be noted when considering medical fitness for surgery include the presence of coexistent comorbid illnesses, specifically diabetes mellitus, hypertension and obstructive sleep apnea (OSA).
All patients must undergo magnetic resonance (MR) imaging of the pituitary gland with the administration of gadolinium contrast, preferably using a dedicated pituitary imaging protocol on a 1.5T or 3T scanner. Most GH secreting pituitary adenomas are readily visible as macroadenomas (>1 cm in size), expanding the sella and extending into the suprasellar cistern. Suprasellar growth and cavernous sinus invasion is classically graded using the Hardy (modified by Wilson) and Knosp systems, respectively. A Knosp grade or 3 or 4 reliably predicts cavernous sinus invasion.
Preoperative computed tomography (CT) is useful in anticipating the anatomy of the nasal cavity, osteomeatal complex and sphenoid sinus, and is routinely performed at our institution. Assessment of the pneumatisation of the sphenoid sinus (sellar, pre-sellar or conchal) allows an estimate of the amount of drilling that will be required to expose the sellar floor. For a complete exposure of the sella recognition of the number and location of intra-sphenoid septae is vital. Other anatomical factors that should be taken into account, particularly in patients with acromegaly, include protrusion of the carotid artery into the sphenoid sinus space, dehiscence of the wall of the carotid canal and the inter-carotid distance. For repeat/revision transsphenoidal surgery, CT scans are indispensable in studying the extent of bony resection performed at the previous operation and intraoperative navigation may prove invaluable in avoiding vascular injury.
Steroid cover for surgery
In the past, perioperative steroids were administered for all patients undergoing transsphenoidal surgery. While this practice is still followed in some centres, an increased incidence of postoperative diabetes insipidus and difficulties in assessing steroid dependency after surgery has questioned the necessity of routine steroid cover, particularly in eucortisolemic patients. Over the last 3 decades, there has been a gradual trend towards a “steroid-sparing protocol” in these patients based on their preoperative adrenal reserve. At our institution, only patients with hypocortisolemia (serum cortisol <3.6 mcg/dl) or above 60 years of age receive perioperative steroids. In patients with equivocal cortisol levels (3.6-16 mcg/ml), only a negative response to the short synacthen test (serum cortisol levels <18 mcg/dl 60 minutes following intravenous administration of 250 mcg of synthetic ACTH) warrants steroid cover. Patients with a positive result (post-synacthen cortisol >18 mcg/dl) do not receive steroids, but their cortisol levels are monitored daily for the first three postoperative days.
Compared to patients with other pituitary tumors, patients with GH-secreting adenomas pose specific challenges with regard to airway management at the surgery., Laryngoscopy and endotracheal intubation are made difficult due to soft tissue hypertrophy in the upper airways, macroglossia, prognathism and higher Mallampati classes. Concomitant obstructive sleep apnea should alert the anaesthesiologist to potential problems with mask ventilation, intubation and extubation. Flexible fibre-optic intubation may be helpful in these patients, with awake fibre-optic intubation reserved for particularly difficult airways. Hypertensive patients can have a surge in blood pressure during the nasal phase of the surgery. Nasal packing with topical lignocaine attenuates this response.
Intraoperative lumbar drainage
The placement of a lumbar subarachnoid drain preoperatively has been suggested by Mehta and Oldfield as a relatively simple and safe and measure to reduce the risk of intraoperative cerebrospinal fluid (CSF) leaks during transsphenoidal surgery. The efficacy of this method has been confirmed by a randomized controlled trial published from our institution; nevertheless, insertion of a lumbar drain remains an invasive procedure with potential complications. Therefore, it may be reasonable to reserve the use of lumbar drainage for patients at high risk of intraoperative CSF leaks, including patients with obesity or marked suprasellar extension towards the floor of the third ventricle.
Historically, the earliest attempts to resect pituitary tumors were via the transcranial route. The trans nasal approach, pioneered by Schloffer, Kanavel and Hirsch, saw significant advancements in the early 20th century. Cushing himself first used this approach to treat a patient with acromegaly in 1909. However, it gradually fell out of favour, as most neurosurgeons across the world returned to trans cranial approaches, till the 1960s when it was resurrected by Guiot and Hardy., Since then, the field has seen further advancements, particularly with the advent of endoscopy in anterior skull base surgery.
Currently, almost all GH secreting pituitary adenomas are addressed transsphenoidally, and this may be accomplished by any of the following techniques: (1) sublabial transseptal, (2) transnasal microsurgical, and (3) endoscopic transsphenoidal. The microsurgical approaches have been used for decades by neurosurgeons, with excellent results, and the surgical techniques have been described in detail in previous publications. Over the last two decades, endoscopic resection has rapidly become popular for these tumors, and, in 2009, we completed a full transition to endoscopic transsphenoidal surgery. Technical nuances of this approach have been described elsewhere, but a brief overview is provided below, in addition to a discussion of aspects specific to GH-secreting pituitary adenomas.
After administration of intravenous antibiotics and induction of general anaesthesia, the patient is placed in the supine position with the head neutral and laterally flexed to the left side on a horseshoe head ring. The head-end of the table is elevated 30 degrees. We prefer a four-hand, bi-nostril technique, since it offers more dynamic views of the sella, and makes surgery relatively easier in acromegalics where the nasal cavity is often narrow. Proponents of the uni-nostril transsphenoidal surgery, however, claim a lower rate of postoperative nasal complications, such as epistaxis. The nasal turbinates are frequently hypertrophied in patients with acromegaly and a middle turbinectomy may be performed to enhance access, especially in cases with marked septal deviations and tumors that have parasellar extension. A linear longitudinal mucosal incision is placed on the upper part of the nasal septum to allow for removal of the vomer and a posterior septectomy. This nasal incision can be converted into a flap to elevate a nasoseptal graft for dural repair if required at the end of the surgery.
The sphenoid ostia are identified and enlarged medially with a Kerrison's punch. Septations within the sphenoid sinus and the bony sella floor are drilled down to expose the edges of the cavernous sinus on either side. In cases with substantial suprasellar extension, the bone over the medial opticocarotid recesses is removed to improve access to the suprasellar portion. The dura is opened as a square and submitted separately for histopathology. The tumor within the sella is removed with biopsy forceps and submitted for histopathology. Further tumor removal continues with two suction tips, one curved and one straight and pituitary forceps for more firm tissue. The normal pituitary gland is usually displaced to the periphery by the tumor, and its position can be anticipated by studying the preoperative MRI. The normal gland must be preserved as far as possible, and the decision to carry out intra-capsular versus extra-capsular tumor resection may represent a slight trade-off between retaining pituitary function and achieving biochemical remission. Furthermore, care is taken to not injure the suprasellar arachnoid that gradually descends down as the sella is progressively decompressed. A less turgid arachnoid pouch is less susceptible to tearing during dissection, and CSF drainage is helpful, if a lumbar drain has been placed. Angled endoscopes are used to inspect the suprasellar and parasellar regions. Tumor in the cavernous sinus may be explored at this stage, although it is perhaps prudent to not attempt exploration of the sinus lateral to the ICA. Microinvasion of the medial wall of the cavernous sinus may justify excision of the wall after cutting the pituitary suspensory ligaments and cauterizing and cutting the inferior hypophyseal artery.
After obtaining haemostasis, the sella is loosely packed with an abdominal fat graft. If a CSF leak has occurred at surgery, the reconstruction of the sellar floor is often reinforced with a pedicled nasoseptal mucosal graft, with fibrin glue to seal the edges.
Intraoperative adjuncts to transsphenoidal surgery
Technological advances in skull base surgery have allowed for the introduction of a number of powerful tools to enhance operative outcomes in patients with acromegaly. The use of a bayonetted micro-Doppler probe is a simple and effective method to insonate and localize the internal carotid artery prior to dural opening. MRI or CT-based neuronavigation may also be used to guide transsphenoidal surgery and avoid vascular injury, particularly in re-operations, where the normal anatomy is often distorted.,
Intraoperative MRI has been found to be particularly useful in the detection of “unexpected residual tumor” in patients undergoing transsphenoidal surgery. Netuka et al. reported an 11.3% increase in overall remission rate after using intraoperative MRI to gauge the completeness of resection in patients undergoing surgery for acromegaly. However, intraoperative MRI technology remains prohibitively expensive and logistically complex, and may be supplanted by high-quality endoscopy instead.
Special approaches for difficult cases
The standard transsphenoidal approach may not be adequate to remove large and invasive GH-secreting pituitary tumors and may necessarily have to be modified according to tumor morphology. The extended transplanum approach is helpful in improving access to tumor in the suprasellar cistern. For improved access to the cavernous sinus, the transethmoidal-transsphenoidal, transmaxillary-transsphenoidal and expanded transsphenoidal approaches have been suggested.,, Kitano et al. achieved remission in 67% of patients with invasive GH secreting macroadenomas using a posterior ethmoidectomy to improve lateral exposure and thereby approach the cavernous sinus through its inferior wall. These complex skull base approaches, however, are technically demanding and there remains a risk of excessive intraoperative blood loss, vascular or cranial nerve injury and CSF leak. Trans cranial surgery remains an option for large and giant tumors, particularly those extending superolateral to the supraclinoid internal carotid artery; however, it must be remembered that remission is almost never achieved with surgery alone in these cases. Therefore, surgery should aim to decompress the optic apparatus and debulk the tumor, prior to adjuvant medical and radiation therapy.
Complications of surgery
In experienced hands, transsphenoidal surgery can be performed with low rates of morbidity, regardless of technique. Complications of transsphenoidal surgery for acromegaly from select studies are summarized in [Table 1].,,,,,,,,,
Disorders of fluid balance are common after transsphenoidal surgery. Immediate postoperative fluid diuresis is not unusual in patients undergoing surgery for GH-secreting pituitary adenomas, particularly in those who achieve biochemical remission, and must be differentiated from diabetes insipidus. The commonest cause for re-admission following transsphenoidal surgery remains delayed hyponatremia, regardless of the primary pathology. Therefore, serial monitoring of serum electrolytes is of paramount importance, particularly in the first few days after surgery.
When the morbidity of endoscopic and microscopic transsphenoidal surgery are compared, there appears to be a greater incidence of sinonasal complications, but less frequent postoperative hypopituitarism with the former technique. Based on data accrued from a comprehensive literature review by Chen et al., intraoperative CSF leaks also appear to be more frequent in endoscopic versus microscopic transsphenoidal surgery (17.4% versus 2.8%). While this may be due to under-reporting of intraoperative CSF leak in the microsurgical era, there remains no major difference in the rates of postoperative CSF rhinorrhoea.
Early postoperative assessment of remission
The half-life of the GH molecule is less than 30 minutes, and therefore early postoperative growth hormone levels may be used to assess patients for sustained biochemical remission., In a recent study from our institution, regression coefficients obtained from a multivariable statistical model based on early postoperative GH levels and tumor size were used to develop a scoring system that accurately predicted remission at the 3-month follow-up assessment. Although disease status must be formally assessed at least 12 weeks after surgery, early GH assays enable early detection of patients with residual disease, and who, therefore, will require adjuvant treatment. IGF-1 levels on the other hand tend to normalize over a significantly longer period of time after successful transsphenoidal surgery, limiting their use in the early biochemical assessment of remission.
Formal assessment of remission
A discussion on outcomes following surgery for acromegaly must take into consideration the evolving definition of biochemical remission. Criteria for cure have become progressively more rigorous over the last few decades, with the 2010 Cortina consensus defining remission as normalization of serum IGF-1 levels with either a basal GH <1 ng/ml or a nadir GH <0.4 ng/ml following suppression with oral glucose. Freda et al. have reported a higher risk of recurrence in patients with subtle elevations in post-suppression GH levels yet with IGF-1 normalization. This has been incorporated into the 2014 Endocrine Society Clinical Practice guidelines, which suggest that a nadir serum GH <0.14 mcg/L should be considered as “surgical remission,” and a level <1 mcg/L as indicative of “control” and normalization of the mortality risk. This would imply that a larger proportion of patients would be classified as having a residual disease based on current guidelines, as compared to the recommendations published in 2000. The need for such an exacting definition of remission has yet to be supported by long-term follow-up studies, and it is unclear if this increased stringency tends to “over-treat” patients with marginally elevated postoperative GH/IGF-1 levels.
Remission rates across literature
A summary of published studies describing remission rates in patients with acromegaly using the 2010 consensus criteria is provided in [Table 2].,,,,,,,,,,, This indicates remission rates varying widely from 31.9% to 84.9%, perhaps reflecting differing proportions of invasive tumors across various cohorts. Using older criteria, most authors have reported remission rates of 50-75%,,,,,,, which are slightly higher compared to the modest endocrinological outcomes published in more contemporary studies. Studies that have specifically compared microsurgical and endoscopic transsphenoidal surgery have failed to find any statistically significant difference between the two procedures in terms of remission rates., A recent systematic review also yielded similar conclusions.
Predictors of outcome
The most important predictors of remission described in literature include tumor size and volume, cavernous sinus invasion and baseline serum basal GH and IGF-1 levels.,,,,,,, Cavernous sinus invasion is perhaps the most important factor associated with remission. Jane et al. demonstrated a sharp drop-off in remission rates with progressively higher degrees of cavernous sinus invasion.
Surgeon experience and familiarity with transsphenoidal surgery may also play an important role in remission rates. There exists a learning curve in endoscopic skull base surgery, and Hazer et al. estimated that the cut-off point for the number of surgeries needed for a surgeon to improve remission rates was rates were 108 cases.
Colao et al. reported that 3-6 months of pre-treatment with octreotide improved perioperative glycemic control, blood pressure, lipid profiles and remission rates in patients undergoing surgery for acromegaly. However, these observations have not been unequivocally supported by the results of several recent randomized controlled trials.,, Therefore, somatostatin analogue pre-treatment should be primarily reserved for pre-operative optimization of patients with severe acromegaly-related cardiopulmonary and obstructive airway disease, in order to reduce perioperative morbidity.
For patients with residual disease after transsphenoidal surgery for acromegaly, a number of therapeutic options are available. Reoperation for persistently elevated GH/IGF-1 levels after transsphenoidal surgery has historically provided poor outcomes. More recent experience with endoscopic surgery, however, has provided marginally better outcomes with repeat surgery. Nevertheless, re-operation for a residual disease should probably be reserved for patients with surgically accessible residual tumor in the sella. Other possible interventions include stereotactic radiosurgery or fractionated stereotactic radiotherapy which can provide reasonably good disease control after failed transsphenoidal surgery.,, Medical treatment with somatostatin analogues (octreotide, lanreotide), dopamine agonists (cabergoline) or GH receptor antagonists (pegvisomant) are salvage options. However, pharmacotherapy for acromegaly is expensive and necessitates life-long therapy.
At our institution, all neurosurgical patients with acromegaly are managed in consultation with a multidisciplinary team comprising endocrinology, neuro-radiology and radiation oncology. Since 2009, we have dealt with pituitary adenomas using an almost exclusively endoscopic transsphenoidal approach. Using the 2010 Cortina consensus criteria to define remission, we have previously reported our experience with endocrinological outcomes following surgery for acromegaly. In this cohort of 113 patients, with primary GH secreting pituitary adenomas, followed over a mean period of 33.5 months, 86% of tumors were macroadenomas and 43.4% were invasive. Remission was achieved in 28.8% of cases with endoscopic transsphenoidal surgery (n = 66) and in 36.2% of cases with the endonasal microsurgical approach (n = 47). Overall, the most frequent complications included intraoperative CSF leak in 34.5%, postoperative CSF rhinorrhoea in 3.4%, diabetes insipidus in 7.1% and new onset hypopituitarism in 26.5%. Compared to reports from outside the Indian subcontinent, it appears that our patients had larger and more invasive tumors that were less amenable to biochemical remission through surgery alone. [Figure 1] and [Figure 2] provide illustrative examples.
The management of growth-hormone secreting pituitary adenomas is primarily surgical and the overall morbidity of surgery is low., Transsphenoidal surgery, regardless of technique, offers reasonable remission rates in patients with acromegaly, especially in those with smaller and non-invasive tumors. However, modern criteria for remission are stringent, necessitating adjuvant therapy for a significant proportion of patients with postoperative residual disease.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2]
[Table 1], [Table 2]