12 Natural History and Management Options of Nonfunctional Pituitary Adenoma

Vincent Dodson, Neil Majmundar, Wayne D. Hsueh, Jean Anderson Eloy, and James K. Liu

Abstract

Nonfunctional pituitary adenomas are “benign” neoplasms of the pituitary gland which may cause mass effect upon the surrounding neurovascular structures. Symptoms include headaches, visual field defects, and potentially pituitary hormonal disturbances secondary to compression of the pituitary gland and/or stalk. Routine work-up for patients with these lesions includes laboratory testing (including pituitary hormone levels), preoperative visual field testing, and advanced imaging (CT head and MRI brain). Treatment options include endoscopic endonasal transsphenoidal surgery and radiosurgery.

Pituitary adenomas are benign neoplasms of the pituitary gland, which can cause mass effect upon surrounding neurovascular structures. The prevalence ranges between 14 and 54%, with equal distribution between genders and age groups.1^{,​ 2} Pituitary adenomas may be functional (actively hormone secreting) or nonfunctional (inactive). The symptoms exhibited by functional pituitary adenomas are directly associated with the hormone being secreted. Nonfunctional pituitary adenomas (NFPAs) are often asymptomatic or demonstrate symptoms secondary to mass effect (Fig. 12.1), which includes headaches and visual field defects from optic chiasm compression.³ NFPAs may also cause hypopituitarism as a result of compression of the pituitary gland and stalk, which can result in hypogonadal symptoms such as loss of libido, oligomenorrhea, and erectile dysfunction.⁴

12.2 Selected Papers on the Natural History of NFPAs

●Imran SA, Yip C-E, Papneja N, et al. Analysis and natural history of pituitary incidentalomas. Eur J Endocrinol 2016;175(1):1–9

Patients with NFPAs most commonly present with headaches or symptoms related to pituitary dysfunction, typically hypogonadism.6 Most discovered NFPAs are greater than 10 mm as these are more likely to be symptomatic.⁵ NFPAs may be further classified by their size. Tumors less than 10 mm are referred to as microadenomas and tumors greater than 10 mm are referred to as macroadenomas. While studies examining the natural course of untreated NFPAs are scarce, macroadenomas are more likely to exhibit tumor growth and complications.⁶

Growth rates of NFPAs can vary widely, with most NFPAs either increasing in size or remaining the same size. While many patients who are found to have growth of their NFPAs may remain asymptomatic, they may experience symptoms secondary to mass effect upon the local neurovascular structures. These symptoms include visual field deficits secondary to compression of the optic apparatus, hypopituitarism secondary to mass effect on the gland or stalk, and pituitary apoplexy secondary to intratumoral hemorrhage and/or infarction. While hypopituitarism may be associated with tumor growth, Imran et al found that the presentation of secondary hormonal deficiency was not related to initial size of the NFPA at presentation, and most nonsurgical patients (88%) experienced no change in their secondary hormonal deficiency on follow-up.⁵

Pituitary apoplexy, although rare, is the most serious complication that can lead to ophthalmoplegia and vision loss. Fernández-Balsells et al found in their meta-analysis that the incidence of pituitary apoplexy is 0.2 per 100 person-years.⁶ Treatment with hormone analogs is a risk factor for developing apoplexy as the analogs can abruptly cause an increase in metabolic activity and subsequent tumor infarction.⁷ Multiple retrospective studies of patients with pituitary adenomas found that having an NFPA was a risk factor among several others for pituitary apoplexy.^{8,​ 9,​ 10} Another exceedingly rare sequela of NFPAs is the malignant transformation to nonfunctioning pituitary carcinomas. Prognosis of this condition is generally poor, and the pathogenesis of the malignant transformation of NFPAs is not well understood.¹¹

Although all risk factors for the growth of NFPAs are not well understood, a retrospective study found that NFPAs have a higher risk of enlargement compared to nonpituitary sellar masses, such as Rathke’s cleft cysts, craniopharyngiomas, and meningiomas.⁵ Among NFPAs, macroadenomas are also at a higher risk of growth than microadenomas.^{6,​ 12} Furthermore, age may play a role in the rate of tumor growth.¹³ Watts et al found in their retrospective analysis of surgically treated patients with NFPAs that age was a significant risk factor for tumor regrowth, with younger patients more likely to experience a higher rate of regrowth. Their study found for every year older a patient was at presentation, there was an associated 3% reduction in regrowth rate. When patients were grouped by age, they found that patients who were  ≤ 41 years old had a 4.2 times higher regrowth rate than patients who were  ≥ 41 years old.¹³ Remission after surgery is also lowest in patients with NFPAs compared to patients with functioning adenomas, perhaps because they are more likely discovered when they have become too big to make curative surgery a possibility.¹⁴

12.4 Selected Papers on the Management Options of NFPAs

●Lucas JW, Bodach ME, Tumialan LM, et al. Congress of neurological surgeons systematic review and evidence-based guideline on primary management of patients with nonfunctioning pituitary adenomas. Neurosurgery 2016;79(4):E533–E535

●Kuo JS, Barkhoudarian G, Farrell CJ, 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;79(4):E536–E538

12.5 Management Options

12.5.1 Endocrine Evaluation

The first step in evaluating a pituitary adenoma is to determine whether it is a functioning or a nonfunctioning adenoma. This step is critical in determining whether the pituitary adenoma is a prolactinoma, as prolactinomas can be treated medically in most cases, whereas NFPAs are more often treated surgically.¹⁷ Given that the development of secondary hormonal deficiency is a common complication in patients presenting with NFPAs, these patients should receive routine endocrine evaluation. NFPAs may cause hyperprolactinemia by causing compression of the pituitary stalk disrupting dopamine release. While no specific cutoff exists for serum prolactin levels to make the distinction between prolactinomas and NFPAs, patients with prolactinomas generally have higher levels of serum prolactin than those with NFPAs and concomitant hyperprolactinemia. Hong et al found that patients with NFPAs and concomitant hyperprolactinemia generally have serum prolactin levels less than 100 ng/mL.¹⁸

In addition to potentially causing hyperprolactinemia, NFPAs may also cause deficiencies of anterior pituitary function. Growth hormone deficiency, central hypothyroidism, central hypogonadism, and adrenal insufficiency have all been reported as possible sequelae of NFPAs. As the prevalence of these deficiencies is common in patients with NFPAs, routine endocrine axis testing is indicated for newly diagnosed patients and during follow-up.

12.5.2 Ophthalmologic Evaluation

The preoperative assessment of vision in patients with NFPAs can be helpful in tracking postoperative visual improvement. Visual testing is particularly important in older patients, as visual symptoms may go unnoticed in this age group.¹⁹

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