Introduction

Trans-sphenoidal selective adenomectomy is the primary therapy for Cushing's disease in humans. The most common approach in humans is by the standard microsurgical submucosal trans-septal trans-sphenoidal procedure using a neurosurgical operating microscope. There are many virtues of the midline trans-sphenoidal approach. Most importantly, it is the least traumatic route of surgical access to the sella. The lack of visual scars, lower morbidity and mortality as compared with transcranial procedures, the necessity of only a brief hospital stay and the relatively brief recuperative period add to the procedure's appeal. More and more human pituitary surgeons employ the pure endoscopic endonasal trans-sphenoidal surgical approach for pituitary tumour removal using rigid endoscopes. The pure endoscopic approach is facilitated by the air-filled sphenoid sinus, which is only separated by a thin bony floor from the pituitary fossa.

In dogs the most common method of treatment for Cushing's disease or pituitary-dependent hypercortisolism (PDH) remains medical treatment with mitotane (o,p'-DDD) or trilostane. However, medical therapy leaves the pituitary adenoma untreated. Also, it may be hypothesised that the removal of the chronic negative feedback exerted by the glucocorticoid excess at the pituitary level, may actually stimulate pituitary tumour proliferation and expansion.

At Utrecht University trans-sphenoidal hypophysectomy was restarted in 1993 and has become an important addition in the management of Cushing's disease in the Netherlands (and occasionally for patients coming from other European countries). Until now 300 dogs and 20 cats have undergone pituitary surgery. Surprisingly, pituitary surgery in dogs and cats is only advocated in a few other institutions besides the Netherlands (Japan and only very recently the USA). In dogs the indications for pituitary surgery include pituitary corticotrophic adenomas (causing Cushing's disease), debulking of clinically non-functioning pituitary macroadenomas (causing diabetes insipidus or central neurological signs by the tumour mass effect) and occasionally sellar meningiomas.

Pituitary Imaging

Computed tomography (CT) and magnetic resonance imaging (MRI) visualise the pituitary size and the surgical landmarks that are a prerequisite for pituitary surgery. Since the surgical landmarks are bone structures, they are more difficult to discern on MR images than on CT images. CT has proven to be practical, fast and accurate for detection of pituitary abnormalities (Figure 1). Surgical localisation of the pituitary gland in the various canine and feline skull types is dependent on the continuous visual assessment of typical bone features during the trans-sphenoidal approach and relating those, real-time, to the CT images in the operating room. The enhancement pattern of the neurohypophysis during dynamic contrast-enhanced CT has been called the 'pituitary flush'. The displacement, distortion, or disappearance of the pituitary 'flush sign' in dynamic CT examinations can be used to confirm left or right-sided lateralisation of (micro)adenomas.

Figure 1. Transverse contrast-enhanced computed tomography of the skull of a dog with Cushing's disease due to a pituitary adenoma, before (A) and 8 weeks after trans-sphenoidal hypophysectomy (B).

Surgical Technique

Pituitary surgical techniques include selective removal of the pituitary adenoma (adenomectomy), removal of the adenohypophysis (adenohypophysectomy), removal of a significant part of pituitary tumour mass in the case of a macroadenoma (pituitary debulking) or complete removal of the pituitary gland including the tumour (hypophysectomy). Hypophysectomy in the dog and cat is performed by the midline transoral, transnasopharyngeal, trans-sphenoidal, microsurgical approach with the animal in sternal recumbency. Access to the pituitary fossa is obtained with a burr. An operating loupe or videoscope is used to provide magnification. Bone punches are used to enlarge the opening created in the inner cortical lamina of the sphenoid bone. Following incision of the dura mater, the pituitary adenoma is extracted through the dural opening using fine neurosurgical grasping forceps and suction. In most cases the complete adenohypophysis is usually affected by the tumour and there is no sharp definition between adenoma and normal pituitary tissue. Unlike in humans with Cushing's disease, well defined pituitary (micro)adenomas are rare in dogs and cats. The hypophysectomy is considered complete when there is an unobstructed view of the ventral hypothalamic surface and the opening to the third ventricle, and there are no pituitary remnants upon exploration of the extensions of the hypophyseal fossa. The pituitary fossa can also be inspected for pituitary tumour remnants using rigid endoscopes, e.g., an endoscope with a diameter of 2.7 mm and a 30-degree viewing angle. In dogs with giant (> 2 cm) pituitary adenomas, the aim is to remove as much of the tumour tissue as possible to reduce the mass effect (debulking).

Postoperative intensive care includes close monitoring of vital functions, plasma electrolytes (sodium and potassium), plasma osmolality and central venous pressure. Oral water intake is encouraged as soon as possible. Postoperative medication includes antibiotics and analgesics. Hormone replacement consists of hydrocortisone (1 mg/ kg i.v. q6h) and desmopressin, a vasopressin analogue (4 µg administered as a drop into the conjunctival sac q8h for 2 weeks). When the dog has resumed eating and drinking, oral replacement therapy is started: cortisone acetate (1 mg/kg q12h) and thyroxine (15 µg/kg q12h). Over a period of 4 weeks the dose of cortisone acetate is gradually tapered to 0.25 mg/kg q12h. Desmopressin (0.01%) is administered for 2 weeks, 1 drop into the conjunctival sac q8h.

Results and Complications

The efficacy of trans-sphenoidal hypophysectomy in the treatment of dogs with PDH has been investigated in a prospective study in 181 dogs with a median age of 9 years. The 1-, 2-, 3- and 4-year estimated survival rates were 86%, 83%, 80% and 79%, respectively. Treatment failures included postoperative mortalities (= death within 4 weeks after surgery irrespective of the cause of death, 14 dogs) and incomplete hypophysectomies (12 dogs). The 1-, 2-, 3- and 4-year estimated relapse-free fractions were 90%, 77%, 72% and 62%, respectively. Survival and disease-free fractions after hypophysectomy were markedly higher in dogs with non-enlarged pituitaries than in dogs with enlarged pituitaries. The main postoperative complications after hypophysectomy are reduction in tear production (31%) and prolonged diabetes insipidus (53%). Tear production restored to normal values in 79% of the affected dogs over a median period of 9 weeks. Diabetes insipidus occurred more frequently in dogs with enlarged pituitaries than in dogs with non-enlarged pituitaries and was permanent in 22% of the dogs. The results compare favourably with those of 129 dogs treated with o,p'-DDD in the same institution in another timeframe. With longer follow-up time, hypophysectomy leads to better results than o,p'-DDD treatment.

Adrenocortical Function After Hypophysectomy

Adrenocortical function after hypophysectomy can easily be measured using the basal urinary cortisol/creatinine ratio (UCCR) in samples collected at home. When the patient leaves the hospital, usually 3 days after surgery, owners receive tubes for urine collection at 2 weeks, 8 weeks, 6 months and 1 year after surgery. Thereafter, yearly assessment of adrenocortical function is advised. Urine samples are collected at home when the dog has been free of cortisone medication for 24 hours. The early (< 8 weeks) UCCR has prognostic value when considering long-term survival and disease-free fractions. In dogs with early postoperative UCCR < 5 x 10^-6, the survival and disease-free fractions are greater than in dogs with early postoperative values between 5 and 10 x 10^-6.

Pituitary Surgery in Cats

The indications for trans-sphenoidal hypophysectomy in cats are: Cushing's disease caused by an adrenocorticotropic hormone (ACTH)-cell pituitary adenoma or acromegaly caused by a growth hormone (GH)-cell pituitary adenoma. Both conditions in cats are usually accompanied by diabetes mellitus requiring insulin administration. Trans-sphenoidal hypophysectomy has a higher morbidity and mortality in cats with PDH than in dogs. In cats with acromegaly with concurrent diabetes mellitus, hypophysectomy has an excellent prognosis resulting in disappearance of diabetes mellitus, discontinuation of insulin administration within 1–4 weeks after surgery, and normalisation of GH and insulin-like growth factor (IGF)-1 levels.

References

1.  Hanson JM, van't Hoofd MM, et al. Efficacy of transsphenoidal hypophysectomy in treatment of dogs with pituitary-dependent hyperadrenocorticism. Journal of Veterinary Internal Medicine 2005;19:687–694.

2.  Hanson JM, Teske E, et al. Prognostic factors for outcome after transsphenoidal hypophysectomy in dogs with pituitary-dependent hyperadrenocorticism. Journal of Neurosurgery 2007;107:830–840.

3.  Hara Y, Teshima T, et al. Efficacy of transsphenoidal surgery on endocrinological status and serum chemistry parameters in dogs with Cushing's disease. The Journal of Veterinary Medical Science 2010;72:397–404.

4.  Meij BP, Auriemma E, et al. Successful treatment of acromegaly in a diabetic cat with transsphenoidal hypophysectomy. Journal of Feline Medicine and Surgery 2010;12:406–410.

5.  Meij BP, Voorhout G, et al. Progress in transsphenoidal hypophysectomy for treatment of pituitary-dependent hyperadrenocorticism in dogs and cats. Molecular Cellular Endocrinology 2002;197:89–96.