Non Functioning Adenoma

 Dr Carmela Caputo1and Dr Warrick Inder2 (Endocrinologists)
1Department of Endocrinology,St Vincent’s Hospital, Fitzroy, Melbourne and 2Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane

Contents

Case

A 57 year old man attended the local eye hospital with a one week history of decreasing vision in the left eye. As part of his tests he had a “visual field test” which showed an abnormality. The tests showed that he had absent vision in the part of the left visual field and some minor areas of decreased vision in the right visual field(figure 1).

One of the causes of this particular type of visual field loss is due to a large pituitary adenoma,so this man was referred urgently for a pituitary MRI scan. He was found to have a very large pituitary adenoma compressing the optic nerve above it, thus causing the visual changes (figure 2). He was then referred to the endocrinology service at St Vincent’s Hospital. He did not have any headaches and did not complain of any symptoms such as tiredness, weight gain or low libido.

His examination looking for characteristic appearance of certain hormonal abnormalities and his appearance was completely normal. He then had some blood tests checking for pituitary hormones. His blood tests for pituitary hormones did not show any hormone deficiencies or excessive hormones. Based on his clinical examination and blood tests, the adenoma was assessed as a “non functioning adenoma”.

As the adenoma was large and causing visual problems, he underwent pituitary surgery. The technique used for surgery was via the nasal passage (trans-sphenoidal surgery). There were no post operative complications encountered and he was discharged home after 5 days. After surgery he was assessed in clinic and his hormone profile continued to be normal, so he did not require any hormone replacement.

A routine MRI was undertaken a month post-operatively which showed that there was still a large amount of adenoma that could safely be removed by surgery again, so he went onto have a second procedure (figure 3). The second operation was successful in removing all visible adenoma. There was no residual adenoma present on the follow up MRI scan (see figure 4). His vision improved and returned to normal.On retesting his pituitary hormones, his pituitary function still remains normal. He continues to be followed up in clinic and will have a repeat MRI scan in 12 months to assess for any new growth.

Definition

Pituitary adenomas (tumours) are benign growths of the anterior pituitary gland. They are the commonest cause of all brain tumours in adults. In one Belgium study, 1 in 1026 people had clinically managed pituitary tumours. In Iceland, it has been recently fount to be even more common, occurring  in 1 in 865 people. In Victoria (population 5.5 million), this would equate well  over 5000 cases. 

Depending on which cell type predominates, these tumours may either produce no hormone (non functioning adenomas - as in the above mentioned case) or excessive amounts of one or more hormones. The adenomas that secrete excessive hormones include prolactinomas (secrete prolactin), growth hormone secreting tumours (leading toa condition called acromegaly), ACTH secreting tumours (resulting in Cushing’s disease) and more rarely TSH secreting tumours (TSHoma). By far, the commonest types are prolactinoma and non functioning adenomas. Acromegalyoccurs in 10-15%, Cushing’s Disease in 5%, and TSHoms extremely rare (<1%).

Pituitary adenomas are categorised by size on MRI scanning:  adenomas <1cm are microadenomas and those ≥ than 1cm are macroadenomas.

Non Functioning Microadenoma (<1cm)

With the wide spread availability of brain MRI scans, microadenomas are discovered with increased frequency in the community as incidental findings when scans are being done for another reason. Microadenomas are usually too small to be seen on conventional CT scans of the brain. 

As non functioning microadenomas are small, they do not compress surrounding brain structures, do not cause headaches or visual problems, and are not usually associated with hormone deficiencies. When an incidental microadenoma is found, it is important for an endocrinologist to investigate if the adenoma is indeed a non functioning adenoma or one that is producing excessive pituitary hormones. This is done by taking a history, examining a patient looking for certain features, and arranging specific blood tests.

It has been shown from some observational studies that non functioning microadenomas rarely grow overtime. Thus, the management of these adenomas involves a repeat MRI scan  12 months later, and then at 3-5 years to ensure there hasn’t been any increase in size.


Non Functioning Macroadenomas (≥1cm)

The remainder of this article will be related to the presentation and management of non functioning macroadenomas (NFAs).


Presentation

Due to the larger size of these adenomas, people with NFAs usually present with

     1)   Headaches or visual problems (due to size of the adenoma)
     2)   Hormone deficiencies

However, as with microadenomas, MRI scans are also detecting more frequent incidental macroadenomas before they cause any symptoms. At St Vincent’s Hospital, we found that 28% percent of people presented with an incidental macroadenoma. The rest,presented with symptoms related to the adenoma.

Symptoms may arise because of the enlarging adenoma pressing on surrounding structures, most importantly the nerves (optic chiasm) which lie above the normal pituitary gland that carry signals from the eyes to the brain (the optic nerves). If the adenoma enlarges upward, this results in visual problems commonly known as visual field defects or less commonly loss of vision. In our series at St Vincent’s Hospital of 177 patients, 69% of people had visual abnormalities at presentation.

Headache is a common symptom at presentation, which also usually relates to direct pressure from the enlarging adenoma and can be found in up to 64% people who present with symtoms (St Vincent’s Hospital series).

Hormone Deficiencies

The normal pituitary gland’s major function is to control hormone production of several other glands. This includes the thyroid gland in the neck, the adrenal glands on top of the kidneys, and the glands which regulate sexual function (testes in men and ovaries in women) (table 1). 

When a pituitary adenoma enlarges, it may block the signals coming to the pituitary from other parts of the brain, leading to a reduction in the pituitary hormones which control these other glands. 



Table 1.  Anterior Pituitary Hormones

Pituitary Hormone
Action
Deficiency
Replacement
ACTH
Stimulates the adrenal glands to make cortisol
Cortisol is a stress hormone. Prolonged deficiency can be life threatening
Available: usually as hydrocortisone, cortisol acetate or prednisolone
 
 
 
 
TSH
Stimulates the thyroid gland to make thyroid hormone (T4 and T3).
Deficiency can lead to slowing down of numerous bodily functions.
Available: usually given as T4 replacement called thyroxine.
 
 
 
 
Gonadotrophins (FSH and LH)
Stimulates the testes in men to make sperm and testosterone. Stimulates the ovaries in women to ovulate and produce estrogen.
Deficiency leads to infertility and has effects on bone health.
FSH and LH are available as injections if fertility required. But usually the end hormone testosterone and estrogen can be replaced.
 
 
 
 
Growth Hormone (GH)
Stimulates the liver to produce IGF-1. This is required for growth in children
Deficiency in children results in reduced height and weight gain. In adults it can lead to a reduced quality of life.
Synthetic GH available as an daily injection
 
 
 
 
Prolactin
Role in stimulating milk production in the breast for breast feeding women
Usually slightly elevated in pituitary adenomas. When elevated if can lead to reduced gonadotrophin secretion from the pituitary.
Medical treatment available to lower prolactin levels but rarely used for non functioning adenomas.
 
 
 
 

Hormone deficiencies can occur in one or more pituitary hormones. The term hypopituitary generally refers to the condition of having 2 or more pituitary hormones which are deficient. The most important hormones that need to be replaced urgently if deficient are cortisol (made by the adrenal glands) and thyroid hormone, as these can lead to life threatening conditions if left untreated for prolonged periods.

Prolactin is the one pituitary hormone that may be elevated instead of deficient. This is due to the different mechanism of secretion from the pituitary gland compared to the other hormones.

Sex Hormones

The symptoms related to gonadotrophin deficiencies (FSH and LH) depend on the age and sex of a person. The sex hormones are the most common hormones to be deficient when people first present and also after having pituitary surgery.

Women of child bearing age come to prompt medical attention due to irregular or absent menstruation. This occurs either as a result of an elevated prolactin level (which causes a suppression of gonadotrophins), or as a direct effect of a FSH and LH deficiency due to the size of the pituitary adenoma. Deficiency of the gonadotrophin hormones result in menstrual irregularities by impairing ovulation by the ovaries. 

After the menopause, women no longer have menstrual periods and so they often present with other features. They usually present with headaches, visual field problems or as an incidental finding on brain MRI scans. In our own series, almost 50% of postmenopausal women presented incidentally as opposed to 15% of younger females and 23% of males.

Men usually present much later in the course of the disease, and are more likely to have hormone deficiencies. Doctors need to ask men specific questions about difficulties having an erection or lack of sex drive as many are usually reluctant or embarrassed to volunteer this information. Gonadotrophin deficiency in men leads to impaired sperm production (and thus infertility), but also testosterone deficiency. The testosterone deficiency can reduce a man’s libido, muscle strength and sense of well being.

In the long term,deficiencies of estrogen in women and testosterone in men can also lead to thinning of the bones (osteoporosis).

Apoplexy

“Apoplexy” occurs when there is sudden bleeding or circulation blockage within a pituitary adenoma,very similar to what happens to the brain during a stroke. There is no way of predicting in whom this occurs. Apoplexy results in a sudden expansion of the adenoma,and thus usually presents dramatically with severe headache, double vision, loss of vision, nausea, vomiting and drowsiness. This can occur in up to 5-10%at presentation. In our own series, this occurred in 11% of patients and was more likely to occur in men. 

In most situations, people who present with apoplexy are not aware that they have a pituitary adenoma, and this is their first presentation. Anyone who has a very large adenoma that is known about, should be warned that if they experience a sudden severe headache, to present to hospital for an urgent MRI or CAT scan which can quickly if there has been a change in the adenoma size. But this is actually extremely rare event to happen in people already known to have an adenoma.


Management of NFAs

The management of NFAs is usually directed by a team of doctors (called a Multidisciplinary Team), which primary consists of the endocrinologist and the neurosurgeon.


First line treatment: Surgery

If a NFA is not causing any compromise to the visual pathways, it is possible to carefully monitor the adenoma for growth with repeated MRI scans. Recent Australian research has shown that the growth rate over the first 2 years predicts those patients that will go on to require surgery. Those tumour that remain stable in size or grow very slowly are unlikely to need an operation. However, the primary treatment for NFAs is surgical removal which is undertaken when the NFA grows significantly during follow up or when there is an effect on vision. The aim of surgery is to restore the lost vision and remove as much adenoma as possible. 

Modern techniques for surgery include the trans-sphenoidal approach which is approaching the pituitary gland via the nose. The best outcome for pituitary surgery is when the operation is undertaken by a neurosurgeon with a special interest in pituitary surgery who performs more than 25 such operations in a year.

The risk of infection and bleeding from surgery are very low (<1%). Post surgery hormonal imbalances causing either water loss (Diabetes Insipidus) or wate rgain (Syndrome of Inappropriate Antidiuretic hormone, SIADH) can occur temporarily, and is carefully managed by medication (DDAVP) or water restriction respectively. Usually these changes in water balance are temporary, but permanent diabetes insipidus is seen in a small number of patients. We found 7% of people had permanent diabetes insipidus in our series at St Vincent’s Hospital, which is similar to other reports.

If the NFA is large, there may be some difficulty removing the entire adenoma in the first operation. Usually at 4-6 weeks after surgery the MRI is repeated to look for any residual adenoma, and if present, consideration is made for repeat surgery, as in our presented case.

Surgery cannot remove adenoma that has grown within the cavernous sinuses (areas beside the pituitary gland where the carotid arteries and important nerves go through) due to the danger of damaging these structures. In this situation, then the adenoma is assessed for further growth and a decision for radiotherapy treatment is considered. In our extensive series at St Vincent’s Hospital, we found it is common to have some residual adenoma left after surgery, and this occurred in61% of patients. When residual adenoma is present, there is a chance that it can grow again, and this happened in 40% of our patients over an observation time of 4 years. Importantly only half of these patients needed a second treatment (either more surgery or radiotherapy) and the rest were observed for further growth. In patients where the adenoma has been completely removed after the 1st operation, the chance of it regrowing is very low at 12.5%.As adenoma can return, follow up with occasional MRI scans is required.

In the event of an adenoma showing growth again, the multidisciplinary team will consider the best management strategies which can include observation, further surgery or the addition of radiotherapy.

Hormone deficiencies can occur post surgery and this is monitored by blood tests. If there is hormone deficiency prior to surgery, it may return to normal post surgery as the pressure on the pituitary gland is released, but in most cases the hormone deficiency continues. Importantly, these hormone deficiencies can be managed by hormonal treatments via the endocrinologist.

Radiotherapy (second line treatment)

Radiotherapy is highly effective at stopping adenoma growth. The adenoma tissue will still be present but its growth will be impaired. Very few patients actually need to go on to have radiotherapy. It is used when… 

  • Further surgery has been considered by the multidisciplinary team as longer desirable due the position of the remaining adenoma (i.e. in the cavernous sinus mentioned above), or
  • To prevent recurrence of more aggressive adenomas that have already shown a tendency to re-grow.

Radiotherapy techniques are changing over time such that the treatment aims to target as much residual adenoma as possible while minimising radiation exposure to other structures in the surrounding areas (called stereotactic radiotherapy). All patients who have been referred for radiotherapy will have a thorough 1st visit with the radiation oncologist to discuss all aspects of the treatment.

Radiotherapy, like surgery, can lead to hormone deficiencies which can occur slowly over years. Anyone who has had radiotherapy needs to have a yearly check of their pituitary gland function by their endocrinologist.

Medical therapy

Currently medical or “drug”therapies are not routinely used for NFAs as they usually do not result ineffective adenoma shrinkage. However new agents are being developed all the time and trials are being undertaken for some of these new drugs within Australia.


Principles of Long term management of NFA

The aims of long term follow up for NFAs are…

  • To monitor recurrence of NFA and
  • To manage hormonal deficiencies

Recurrence

Recurrence of NFA occurs when there is either growth of a residual adenoma or new growth where the adenoma was previously fully removed. This risk of recurrence is actually low. Several series have shown recurrences to occur 13-41%, but there are differences in reporting these figures as there are variable observation times,variable surgeons and different centres, which can all alter the results. Regrowth or recurrence occurred in 29% of all patients in the St Vincent’s series.

Recurrences are usually more likely to occur when there is post operative adenoma present and in younger people. Currently, there is no definitive way of predicting which NFA are likely to grow, so that serial monitoring via MRI scan is required to look for changes in size. Those tumours which show a high growth rate over the first couple of years after surgery are more likely to need further intervention. When recurrences do occur, the Multidisciplinary team will investigate the best course of action for an individual patient.

Repeated surgery is considered if there is a threat to vision or when there is adenoma tissue in the position where the surgeon can easily approach again. When there is tissue in an area not amenable to surgery, consideration is made to undertake radiotherapy, with the aim being to halt ongoing growth.

Managing long term hormone deficiencies

Following up the hormone status of patients with NFAs long term is required. If there is no hormone deficiency post surgical treatment, the hormone status should remain normal. In people with established hormone deficiencies, occasional assessment is required to ensure that the correct doses are continued and any problems identified. Radiotherapy can lead to hormone deficiencies several years down the track, so this too needs to be monitored with annual assessment of pituitary function. 


Figure 1  Visual Field test

The areas shaded darkest are where the patient was unable to see flashing lights. The left eye is affected more so than the right eye. A normal result would be no areas of dark shading apart from the “blind spot”.


Figure 2

MRI scan showing large pituitary adenoma. 

It is protruding upwards where it has compressed

the optic nerves (white arrow). In this slice, the

optic nerve is so thinned out it cannot be seen 

clearly. The adenoma is also protruding downwards

and invading below the “floor” of the where the

pituitary gland is normally positioned (light grey arrow).

 
 

Figure 3

Post operatively, a large amount of adenoma remains.
You can now see the optic nerves above the adenoma
(the grey slither of tissue pointed by the white arrow).

 
   

Figure 4

MRI after 2nd debulking procedure. Excellent post
operative result with no residual adenoma present. The
area of tissue pushed over to the right is probably the
normal pituitary gland (white arrow).