CME (February 2018)
Monthly Self-Study Series

Treatment of Pituitary Adenoma


Dr. CHAN Ping Hon Johnny
MBBS(HK), FCSHK, MMedsc(HK),
FRCSEd, FHKAM(Surgery)
Specialist in Neurosurgery

Introduction

Pituitary adenoma is the commonest pituitary tumour. The prevalence of the pituitary adenoma is about 1 in 865 persons to 1 in 2688 persons. (1) It is benign in nature and the pathogenesis of pituitary adenoma is unknown. The growth rate of this benign tumour is uncertain, it was reported that the tumor volume-doubling periods range from 0.8 to 27.2 years. (2)

The patient may present with unrelated symptoms and pituitary adenoma was picked up in the MRI examination as incidentaloma.

Presentation

The symptoms are related to the local pressure effect and the hormonal state of the pituitary adenoma.


Fig. 1 Microadenoma


Fig. 2 Macroadenoma

When the pituitary adenoma is less than 1cm, it is called microadenoma; (Fig. 1) they usually do not produce any pressure effect and remain asymptomatic. Tumours are called macroadenoma if the size is bigger than 1cm. (Fig. 2)

In the 9 series that reported 454 patients with pituitary incidentalomas, 304 patients (67%) had macroadenomas. (3)

For the pressure effect, the optic nerves and the optic chiasma is located at the superior aspect of the gland, any pituitary tumour enlargement will compressed the optic apparatus causing the visual symptoms.

The visual symptom is the visual field loss on the temporal side, there is decrease in the color differentiation, blurring of the vision. For bigger tumour, it will compress other cranial nerves. It may present with trigeminal neuralgia and diplopia. If the tumour extends superiorly, it may compress the third ventricle and give rise to obstructive hydrocephalus.

Another important presentation is related to the hormone it secreted. The pituitary adenoma is classified as nonfunctioning and functioning.

Nonfunctioning adenoma is defined as no secretion of excess hormones. It comprise about one-third of pituitary adenomas and range from being completely asymptomatic (incidentalomas) to causing significant hypothalamic or pituitary dysfunction and visual or other symptoms due to their large size.

Functioning adenoma is defined as secretion of excess hormone.

The commonest functioning pituitary adenoma are producing prolactin, growth hormone and ACTH, they account for 50%, 10% and 2-6% respectively.

Prolactinoma is more common in female. Female patient will present with oligomenorrhoea or amenorrhoea, infertility, galactorrhoea. Male patient will present with loss of libido, impotence and gynecomastia.

95% of acromegalic patient has pituitary adenoma. (4) The over production of growth hormone in the childhood give rise to gigantism, there will be excessive height prior to the closure of the epiphyses during puberty. For those patient presented late in the adulthood, they will have coarse facial feature, big hands and feet, tongue; systemic involvement like hypertension and diabetic is common. Acromegaly is associated with a two-fold increase in mortality, primarily due to cardiovascular disease; they can be reversed when the hyper secretion of the growth hormone is under control.

ACTH-producing adenoma (Cushing disease) is the cause of Cushing syndrome in about 65% to 70% of cases. 70% of the patient is female. The patients generally present with complication of hypercortisolism, there are weight gain, trunkal obesity, buffalo hump, moon face, facial rash, skin striae and ecchymosis, diabetes mellitus, hypertension, depression and osteoporosis. Cushing syndrome is associated with a 2- to 5-fold increase in mortality.

Diagnosis

The patient suspected to have pituitary tumour should have MRI examination, hormonal evaluation and eye examination.

MRI will confirm the diagnosis, it show the anatomy of the surrounding structure, the size of the nasal cavity, septum, the pituitary stalk, the tumour, the optic apparatus, the cavernous sinus, and the intracranial internal carotid artery. CT may be required to assess the bony structure of the nasal cavity.

There are causes of hyperprolactinaemia other than prolactinoma. Prolactin secretion is inhibited by the neurotransmitter dopamine coming from the hypothalamus, so that hypothalamic or pituitary stalk disease may cause a decrease in inhibition and increase in prolactin levels. It can be found in pregnancy, hypothyroidism, and renal failure. Those medications blocking the dopamine receptor will elevate the prolactin level. They are Phenothiazines, Haloperidol, Tricyclic antidepressants, Reserpine, Methyldopa, Metoclopramide, Verapamil, Serotonin reuptake inhibitors.

If the tumor is very large (>3 cm), the very high prolactin levels (usually >10 000 £gg/L) may rarely saturate the antibodies in some assays, leading to artifactually low or normal results (the "hook effect") and prolactin levels should be rerun at 1:100 dilution to exclude this. (5)

IGF-1 is 90% specific for a growth hormone secreting pituitary tumour, when in doubt, an oral glucose tolerance test should be performed to demonstrate that growth hormone levels cannot be suppressed to less than 1 £gg/L by hyperglycemia.

For the ACTH-secreting tumour, the initial step is to confirm the hypercortisolism. The test is morning cortisol level, which is elevated. Dexamethasone suppression test may also be useful. Often more than one test is required to establish that hypercortisolism is present. (6)

Eye assessment is mandatory which included the visual field examination, visual acuity, and color differentiation. Accurate documentation is required to demonstrate the success of the treatment.

Treatment options

The treatment options are observation, medications, surgery, and radiotherapy.

Observation is usually suitable for those who are asymptomatic, non-functioning pituitary microadenoma. MRI examination and the hormonal evaluation have to be performed in every six months if the patient remains asymptomatic.

Treatment for prolactinoma

For prolactinoma, the goals are fertility and tumour size reduction. Medical therapy is the first choice. Dopamine agonist is effective in shrinkage of the tumour. Cabergoline is more effective than Bromocriptine in tumour shrinkage and has fewer side effects. They may cause nausea and gastrointestinal disturbance. The drawback is long term medication is required. Surgery is an option for macroadenoma when the medical therapy is not effective. 65-80% of patient can achieve normal prolactin level after the surgery.

Both dopamine agonists are safe to use in early pregnancy and are considered US Food and Drug Administration (FDA) class B (no evidence for risk in humans) for pregnant women. (12)

For women with prolactinomas being treated with dopamine agonists, these drugs are usually stopped when a woman becomes pregnant. The high estrogen levels in pregnancy have risks of tumor growth of 21% in macroprolactinoma and of 2% to 3% for those with microprolactinoma. It was restarted if tumors enlarge significantly and causing pressure symptom. In the very rare situation that there is no response to the dopamine agonist and worsening vision, surgery or delivery have to be considered.

Treatment for nonfunctional pituitary adenoma

Surgery is indicated when the tumour size is bigger than 10mm, symptomatic with visual complaint. (7)

The choice of the surgery is craniotomy or transsphenoidal operation. Craniotomy is reserved for giant tumour and complicated case. The majority of the pituitary adenoma can be excised through transnasal transsphenoidal approach.

Treatment for functioning pituitary adenoma

Surgery is the primary therapy.

Patient with Cushing disease caused by pituitary adenomas should be stabilized by medical mean before the surgery. These medications act at different level. It can inhibit ACTH secretion from the pituitary adenoma (Cabergoline, Pasireotide), block cortisol synthesis in the adrenal (Ketoconazole, Metyrapone) or blocks cortisol action at the glucocorticoid receptor (Mifepristone). It can achieve biochemical control in 30-60% of patients. (8)

The common medication use for growth hormone secreting tumour is somatostatin analogues, and it can achieve biochemical control in 20% to 35% of patients.

The cure rates in the 80% to 90% by expert pituitary surgeons and a recurrence rate of 10% to 20%.

Surgery

The transnasal transsphenoidal approach is a minimal invasive surgery using microscope or endoscope. The sphenoid sinus is approached through the nasal route. Once the sphenoid sinus is entered, the sellar that houses the pituitary gland will be identified.

Navigation system and intra-operative MRI can be used for tumour localization; especially for those with small tumour and with difficult anatomy. (9) When all the anatomy is confirmed, the sellar floor is drilled open; the dura is incised. The tumour is dissected away from the normal gland; tumour excision was carried out using suction and curettage. Intra-operative MRI can be used to assess the completeness of the resection. At the end of the operation, there are layers repair and the sellar floor was reconstructed. Sphenoid sinus was packed with autologous fat graft, the nasal mucosa was re-aligned, and the nasal packs were inserted for hemostasis.

Complications of surgery

The complications are CSF leakage 1.5%, vasospasm, carotid artery pseudoaneurysm 0.4% and pan-hypopituitarism 7.2%, Diabetes incipidus 7.6%. (10) CSF- leakage may need lumbar CSF drainage and re-operation to reconstructed the sellar floor and re-pack the sphenoid sinus. For panhypopituitary, patient may require to have long-term hormonal replacement.

Role of radiation therapy

Radiotherapy is indicated for those who are unfit to have surgery, refuse surgery, sizable residual tumour after surgery and residual high hormonal level.

For the post-operative radiotherapy, there is no difference in tumour control whether it was delivered in early phase (within 6 months) or delay phase (after 6 months).

Stereotactic radiotherapy results in faster reduction in hormone secretion and fewer adverse effects than conventional radiotherapy. The risk for hypopituitarism for both types of radiotherapy, reaching 20% by 5 years and 80% by 10 to 15 years. (11) Comparison had been made between radiosurgery and fractional radiotherapy; there is no difference in the tumour control.

For tumour recurrences, radiotherapy is an option for those remain asymptomatic. If pressure effect is evidenced, repeated surgery is indicated.

Conclusion

Pituitary adenoma is the commonest pituitary tumour, comprehensive investigations including the MRI examination; hormonal evaluation and ophthalmology examination have to be done.

Prolactinoma is primarily treated with medication; functioning pituitary adenoma and symptomatic non-functioning pituitary adenoma are treated with surgery.

Radiotherapy is indicated for surgical unfit patient and residual tumour.

Key lessons

Pituitary adenoma is the commonest pituitary tumour.

MRI, hormonal evaluation and eye assessment are essential investigations.

Primary treatment for prolactinoma is medical therapy.

Surgery is indicated for functioning pituitary adenoma

Reference

  1. AgustssonTT, BaldvinsdottirT, JonassonJG,?et al. The epidemiology of pituitary adenomas in Iceland, 1955-2012: a nationwide population-based study. Eur J Endocrinol. 2015;173(5):655-664.

  2. HoneggerJ, ZimmermannS, PsarasT, et al. Growth modelling of nonfunctioning pituitary adenomas in patients referred for surgery. Eur J Endocrinol. 2008;158(3):287-294.

  3. Reincke M, Allolio B, Saeger W, Menzel J, Winkelmann W. The "incidentaloma" of the pituitary gland. JAMA. 1990;263(20):2772-2776.

  4. MelmedS. Medical progress : acromegaly. N Engl J Med. 2006;355(24):2558-2573.

  5. MelmedS, CasanuevaFF, HoffmanAR, et al; Endocrine Society. Diagnosis and treatment of hyperprolactinemia. J Clin Endocrinol Metab. 2011; 96(2):273-288.

  6. Fleseriu M et.al. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline for Pretreatment Endocrine Evaluation of Patients With Nonfunctioning Pituitary Adenomas. Neurosurgery. 2016 Oct;79(4):E527-9.

  7. Kuo JS et.al. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Surgical Techniques and Technologies for the Management of Patients With Nonfunctioning Pituitary Adenomas. Neurosurgery. 2016 Oct;79(4):E536-8.

  8. Molitch ME. Current approaches to the pharmacological management of Cushing disease. Mol Cell Endocrinol. 2015;408(6):185-189.

  9. Chittiboina iMRI During Transsphenoidal Surgery. Neurosurg Clin N Am. 2017 Oct;28(4):499-512.

  10. Alzhrani G, Delayed Complications After Transsphenoidal Surgery for Pituitary Adenomas. World Neurosurg. 2017 Oct 5. pii: S1878-8750

  11. LoefflerJS, ShihHA. Radiationtherapy in the management of pituitary adenomas. J Clin Endocrinol Metab. 2011;96(7):1992-2003.

  12. MolitchME. Endocrinology in pregnancy. EurJ Endocrinol. 015;172(5):R205-R213.

Self-Assessment Questions

Please indicate whether the following statements are true or false.

1. Pituitary adenoma is the commonest pituitary tumour.

2. All the macroadenoma are functioning pituitary adenoma.

3. The commonest functioning pituitary adenoma produce ACTH.

4. Visual symptom in pituitary adenoma is bitemporal visual field loss.

5. All the Cushing syndrome are related to Cushing disease.

6. 50% of acromegalic patient has pituitary adenoma.

7. MRI is the choice for investigation.

8. IGF-1 is specific for growth hormone secreting pituitary adenoma.

9. Primary treatment for prolactinoma is surgery.

10. Radiotherapy is indicated for residual pituitary adenoma.