Pituitary Macroadenomas Treatment & Management

Updated: Mar 24, 2017
  • Author: James R Mulinda, MD, FACP; Chief Editor: George T Griffing, MD  more...
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Treatment

Medical Care

The goal of treatment is complete cure. When this is not attainable, reducing tumor mass, restoring hormone function, and restoring normal vision are attempted using medications, surgery, and radiation. Pituitary macroadenomas often require surgical intervention for cure. The exceptions to this rule are the macroprolactinomas, which usually have an excellent response to medical therapy. The tumor size may be diminished but often does not disappear completely. Medical treatment can play a role in reducing tumor size, controlling hormonal excess, or correcting hormonal deficiency.

Prolactin-secreting macroadenomas respond to dopaminergic agonists. The most frequently employed medications include bromocriptine, cabergoline, and, previously, pergolide. Quinagolide is an alternative with fewer adverse effects than bromocriptine. Prolactin-secreting macroadenomas are so responsive to medical therapy that surgery and radiation often are not used in treatment. Hyperprolactinemia from other lesions interfering with the hypothalamic-pituitary communication also responds to medical therapy.

Pergolide was withdrawn from the US market March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. It is important not to stop pergolide abruptly. Health care professionals should assess patients’ need for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed, another DA should be substituted for pergolide. For more information, see FDA MedWatch Product Safety Alert and Medscape Alerts: Pergolide Withdrawn From US Market.

Growth hormone-secreting tumors should be treated surgically, often followed by radiation therapy. That acromegaly can be treated with surgery alone is very unlikely. However, debulking the tumor is very important. Radiation therapy results in 50% reduction in growth hormone levels within 2 years, followed by an additional 25% in the following 2 years. Thereafter, the growth hormone levels decline more slowly. Therefore, the lower the postoperative growth hormone level, the higher the chance of remission after radiation therapy. Medical treatment is used after surgery to suppress growth hormone secretion, awaiting the occurrence of the effects of radiotherapy. Octreotide is the treatment of choice. A long-acting formulation administered monthly is now available.

Somatostatin must be administered as a continuous infusion, while shorter-acting octreotide is administered tid-qid. Growth hormone receptor antagonists have been another addition to the treatment of acromegaly. Dopamine agonists also may be used but are not as effective as octreotide (approximately 30% of somatotropinomas respond).

Corticotropin-secreting pituitary tumors are treated using surgery and radiation therapy (however, they are rather radioresistant). Medical therapy is reserved for patients whose therapy fails, those who decline other therapy, and those who cannot be treated otherwise. Medical therapy is divided into centrally acting agents that reduce corticotropin release and peripherally acting agents that reduce cortisol secretion or block cortisol action. Centrally acting medications (unfortunately effective in very rare occasions only) include bromocriptine, valproic acid, and cyproheptadine. Peripherally acting agents include ketoconazole, mitotane, and metyrapone. Use of such medications should be in combination with radiotherapy.

Gonadotropin-secreting macroadenomas are treated surgically, followed by radiation. Medical therapy is reserved for those patients who decline definitive treatment. Bromocriptine or octreotide may be used. LH-releasing hormone antagonists may decrease hormone levels but do not affect the tumor size.

Nonsecretory macroadenomas are treated surgically. [3] If surgery is contraindicated, octreotide or bromocriptine may be tried; however, the results are often disappointing.

Thyrotropin-secreting tumors are treated surgically, followed by radiation therapy. Octreotide is quite effective in such tumors and can be used as adjuvant therapy.

Traditional radiotherapy using external beam radiation is used to complement surgery in inoperable cases or in patients declining surgery. The major drawbacks include delayed onset of action and high incidence of panhypopituitarism. [4]

Radiation therapy

Recent studies show the benefits of radiation. [5] Radiosurgery using a gamma knife employs a computer-assisted stereotactic mapping followed by several discrete radiation treatment fields to the tumor. This allows targeting maximal radiation to the tumor while minimizing radiation to the surrounding tissues. Incidence of hypopituitarism is less.

Advances with gamma radiation are associated with a very low incidence of postradiation hypopituitarism if the radiation dose is kept at less than 15 Gy. [6]

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Surgical Care

Pituitary macroadenomas often require surgical extirpation for cure. Transsphenoidal surgery is the approach of choice. [7, 8, 9, 10] Only about 1% of patients require a transcranial approach. Compared with remission rates of 90% in microadenomas, macroadenomas with significant extrasellar extension have remission rates of 15-37% when treated with surgery alone. Radiation therapy and medical treatment often complement surgery. [11]

In a study, Han et al compared the 1-nostril and 2-nostril approaches with transsphenoidal surgery. The researchers concluded that the 1-nostril method is fast, minimally invasive, and adequate for resection of most pituitary adenomas. [12]

In a prospective, randomized study, Mao et al investigated whether treatment with lanreotide prior to transsphenoidal surgery for macroadenomas would improve cure rates in patients with newly diagnosed acromegaly. The study included 49 patients who were administered 4 months of preoperative lanreotide treatment and 49 patients who underwent transsphenoidal surgery without pretreatment. The authors reported a 49% cure rate (24 patients) in the pretreatment group following surgery and an 18.4% cure rate (9 patients) in the nonlanreotide group. Mao et al concluded that in patients with growth hormone–secreting pituitary adenomas, preoperative lanreotide treatment increases cure rates from transsphenoidal surgery. [13]

A study by Przybylowski et al found that in patients with nonfunctioning pituitary macroadenomas, those who underwent primary transsphenoidal resection were more likely to develop syndrome of inappropriate antidiuretic hormone secretion than were those who underwent revision transsphenoidal resection. The primary surgery patients were also more likely to undergo gross-total resection of the lesion than were the revision surgery patients (63% vs 28%, respectively). At 2 and 5 years, however, the latter had similar radiologic progression-free survival rates as the patients who underwent primary surgery (possibly because the revision surgery patients had a greater rate of adjuvant radiation therapy). [14]

A retrospective study by Magro et al of 300 patients indicated that endoscopic transsphenoidal surgery for nonfunctioning pituitary macroadenomas has an acceptable rate of complications. The investigators reported worsening visual and pituitary functions in 2.4% and 13.7% of cases, respectively, permanent postoperative diabetes insipidus in 6.2% of cases, and postoperative meningitis in 3.3% of cases, with a strong link seen between meningitis and intraoperative and postoperative cerebrospinal fluid leaks and surgical times of more than 1 hour. [15]

Adenomas with a dumbbell configuration have been difficult to excise with transsphenoidal surgery. Sankhla et al presented their experience with the extended endoscopic endonasal approach (EEEA), concluding that it is a potentially viable option but additional study is needed. [16]

Intraoperative MRI findings correlate with prognosis of visual deficits after transsphenoidal decompression of the anterior optic pathways. The use of intraoperative MRI may prevent revision surgery for unexpected symptomatic remnants. [17]

A study by Thawani et al found a link between complete resection of pituitary macroadenomas and increased risk of cerebrospinal fluid (CSF) leak. Moreover, use of a fat graft, a nasoseptal flap, or an intraoperative lumbar drain seemed to have limited benefit in lowering the postoperative CSF leak risk. [18]

A study by Johnston et al indicated that in transsphenoidal surgery for Cushing disease, the presence of a macroadenoma and extension of the tumor beyond the pituitary and sella raise the likelihood of nonremission of the disease with the initial surgery and of late recurrence. [19]

In a study of 13 patients, Elhateer et al reported on the effectiveness of fractionated stereotactic radiation therapy (FSRT) in the treatment of macroadenomas. [20] In 12 of the patients, FSRT was employed following tumor resection, while in 1 patient, it served as primary treatment. All but 4 of the patients had nonfunctional macroadenomas. After a median follow-up period of 24 months, the investigators found that local control in the patients was 100% and that 1 patient had a clinically complete response.

According to the authors, the results indicated that FSRT is an effective means of tumor control in patients with pituitary macroadenoma and that it is associated with a low rate of radiation-related morbidity. (No patients were found to have radiation-induced optic neuropathy or radiation-related endocrine dysfunction.) The authors stated, however, that because the study contained so few patients with functioning tumors, they could not judge the hormonal response of macroadenomas to FSRT.

Based on an observational follow-up study (median period, 5.25 y) of 30 patients with pituitary macroadenomas (10 patients with functioning adenomas and 20 with nonfunctioning lesions) that were refractory to conventional surgical and/or medical treatment, Schalin-Jäntti et al also found FSRT to be a beneficial adjuvant therapy for these tumors. [21]

 

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Consultations

When a pituitary macroadenoma is diagnosed, consultations with an endocrinologist, neurosurgeon, neuroradiologist, and neurophthalmologist should be considered.

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