Professor S M Shalet, Professor of Endocrinology, Christie Hospital, Manchester

Before the dialogue let me set the scene with a little background information. Pituitary adenomas (tumours) may be secretory (i.e. they produce hormones) or non-functioning. In order of frequency, the most common hormones secreted by pituitary adenomas that give rise to important clinical effects are Prolactin, Growth hormone (Acromegaly) and corticotrophin (Cushing's disease). The clinical presentation of patients with pituitary adenomas may be divided into three: effects caused by the physical mass of the tumour, such as visual field loss and/or headaches; hormone excess e.g. raised prolactin level leading to Amenorrhoea (loss of periods); and hypopituitarism, i.e. pituitary hormone deficits leading to hypo-adrenalism, Hypothyroidism, growth hormone deficiency, amenorrhoea or loss of libido/impotence.

Pituitary surgery is one therapeutic approach to the management of a pituitary adenoma; others include pituitary Radiotherapy and medical therapy. Often patients require a combination of these therapeutic options to achieve optimum results. Nonetheless, at the present time in the UK it is fair to state that pituitary surgery remains the treatment of choice for acromegaly and Cushing's disease although, increasingly, the dominant popularity of surgery for acromegaly is threatened by advances in drug development. Medical therapy is the treatment of choice for prolactinomas, but a significant minority of patients with a Prolactinoma will undergo surgery. Finally, the vast majority of patients with a non-functioning pituitary adenoma will require pituitary surgery.

Surgical 'cure' of a Pituitary tumour is usually defined as the physical removal of all tumour noted at operation and subsequently radiologically, with biochemical confirmation (i.e. measurement of hormone levels) if dealing with a hormone excess state. Occasional variations of the definition exist, such as in acromegaly, and where this is the case I have explained the alternative meaning in use.

Therefore, leaving aside the standard questions that we might wish to ask of any surgeon about to operate on any part of our anatomy (how long will I be in hospital, what is the mortality rate, what is the risk of a more general complaint such as infection or haemorrhage), what are the specific questions related to pituitary surgery?

What are the questions to ask?

Vision

If I have lost vision, what is the chance that surgery will restore my vision or at least improve it? If vision is normal what is the risk, in the light of the anatomical closeness of the visual pathways to the pituitary adenoma, that vision will deteriorate as a result of surgery? If visual loss is a key feature of the clinical presentation, are there alternative modes of therapy that might improve vision to the same extent as surgery, but be associated with better all round results as far as pituitary function is concerned?

Hormone excess states

Acromegaly

What is the surgical 'cure' rate? How will you define it? If not cured, how successful is the partial tumour removal and does the degree of success matter?

Cushing's disease

What is the surgical 'cure' rate? How will you determine 'cure'? If not cured, can a 'remission' of the Cushing's disease be achieved? In the long term does it matter if a 'remission' rather than 'cure' is achieved? Will I require glucocorticoid replacement post-operatively? If 'cured', is there a risk of a late recurrence?

Prolactinoma

It is my view that, with rare exceptions, surgery is only indicated in patients with prolactinoma if they are intolerant of dopamine agonist (DA) drugs such as Bromocriptine and cabergoline. Therefore I would suggest that the initial key question that the patient needs an answer to is "Do I have a prolactinoma and, if so, why have I not undergone a trial of DA drugs"? If these criteria are satisfied, then the patient needs to know about surgical 'cure' rates and about management strategy if surgery fails to remove all the tumour and restore normal prolactin levels.

Hypopituitarism

What is the risk that surgery might induce hypopituitarism in patients in whom pituitary function is normal or 'partially normal' pre-operatively?

Alternatively - if pituitary function is already damaged pre-operatively through the presence of a mass lesion, what are the chances that the surgery will 'improve' function sufficiently so that the patient may avoid the need for life-long replacement therapy?

Who answers the questions?

It is apparent that the pituitary surgeon is most unlikely to be in a position to answer all of these questions personally! It is only common sense that in centres where pituitary surgery is carried out, pituitary surgeons should work in close collaboration with the local endocrinologists. The data that will help answer many of these questions (e.g. pituitary function test results) will have been collected by the Endocrinologist and it is often the endocrinologist who, in the light of such knowledge, will have been responsible for referring the patient for surgery. Thus, many of these questions will need to be directed towards the endocrinologist, who in the main will be responsible for the audit of most of the outcomes following treatment.

It is my view that the implications from these observations place the endocrinologist at the heart of the management of patients with pituitary adenomas. Unfortunately it is still not uncommon to come across patients with pituitary adenomas who undergo pituitary surgery without having been seen/considered by an endocrinologist, i.e. by direct referral from an ophthalmologist to a neurosurgeon; such referral patterns are inappropriate and need to be changed in the light of the discussion points raised in this article.

Answers from the medical literature

Vision

In the majority of patients (>50%) with non-functioning pituitary adenomas presenting with visual field defects, vision will be improved by pituitary surgery - the exact figures will be influenced by the duration of the visual loss, the exact site and size of the tumour and the skill of the surgeon. In the contrasting presentation of a patient with intact vision undergoing pituitary surgery for adenoma removal, visual field loss as a complication of surgery is very rare (less than 1% of operations). Alternative methods of achieving tumour shrinkage and recovery of vision do exist. The majority of large prolactin-secreting pituitary adenomas shrink in response to DA drug therapy and any visual loss will improve in most patients. Thus partial loss of vision, by itself, is not an absolute indication of the choice of surgical treatment of a pituitary adenoma.

Hormone excess states

Acromegaly

Life expectancy is reduced in untreated acromegaly. The success of pituitary surgery is dependent on the size of adenoma and the pre-operative growth hormone (GH) level. Surgical 'cure' of a GH-secreting micro-adenoma (tumour less than 1 cm in size) can be achieved in approximately 80% of patients; success being defined by a post-operative GH level (>5mU/l) that is 'safe', that is associated with the restoration of a normal life expectancy. Surgery for GH-secreting macro-adenomas (tumours bigger than 1 cm) is less successful in that less than 50% of patients will be left with a post-operative GH level in the 'safe' range (>5mU/l).

Even if a 'safe' GH level cannot be achieved, the degree of reduction in the GH level (e.g. from 100mU/l to 10mU/l), obtained by the surgeon is critical in the context of the treatment to follow. The chances of reducing the GH level down to the 'safe' range with radiotherapy and/or medical treatment is influenced by the pre-treatment GH status - the lower the pre-treatment GH level the greater the chance of achieving a treatment GH level of less than 5mU/l.

Cushing's disease

Most pituitary adenomas associated with Cushing's disease are micro-adenomas. Surgically-induced remission of the disease is achieved in about 80% of patients. A permanent 'cure' is more likely if the post-operative Cortisol level is undetectable. Similarly, if there is a clinical need for glucocorticoid replacement therapy for a prolonged period of time after surgery, this is a favourable indication that a permanent 'cure' of Cushing's disease has been achieved.

Late recurrence of Cushing's disease does occur in up to 20% of patients, but in a significant proportion of these patients true 'cure' was never achieved surgically, only 'remission' of disease. This means that greater clinical, biochemical and radiological surveillance is required for those patients who are no longer Cushingoid, but who do not achieve an undetectable cortisol level post-operatively.

Prolactinoma

Approximately 10-20% of patients with a prolactinoma are intolerant of DA drugs. Surgical 'cure' of a prolactin-secreting micro-adenoma is achieved in about 80% of patients, whereas surgical 'cure' cannot be achieved in the majority of patients with prolactin-secreting macro-adenomas. In order to control the potential growth of the residual tumour many of the latter patients will be offered radiotherapy post-operatively.

Hypopituitarism

In terms of the size of the tumour rather than any associated hormone excess state, pituitary micro-adenomas do not generally cause disruption of normal pituitary function. Macro-adenomas, however, may cause varying degrees of hypopituitarism because of compression of the Hypothalamus, the hypothalamic-pituitary stalk or the pituitary itself. A significant minority of patients (5-30%) will develop new pituitary hormone deficits attributable to the pituitary surgery, whilst the reverse phenomenon of normalisation of previously deficient pituitary function will occur in up to 40% of patients.

Implications

Optimising pituitary surgery is an important goal for the patient in terms of tumour removal and reducing the risk of hypopituitarism; at the same time optimising pituitary surgery is important for the NHS as it reduces expenditure on drugs for hormone suppression, e.g. Somatostatin analogues, and hormone replacement therapy e.g. growth hormone. The best outcome for the surgical treatment of pituitary tumours in any area is achieved with one surgeon specialising in pituitary surgery. Improved results both in terms of tumour removal and residual pituitary function have been shown to correlate with single pituitary surgeon practice and increasing neurosurgical experience. The challenge for The Pituitary Foundation and for every endocrinologist is to ensure that this standard of care is available for every patient in the UK with a pituitary tumour.