Silent Pituitary Adenomas Sarah E. Mayson,
MD
a
, Peter J. Snyder,
MD
b,
*
KEYWORDS Nonfunctioning pituitary adenoma Silent pituitary adenoma Clinically silent pituitary adenoma KEY POINTS Nonfunctioning, or silent, pituitary adenomas can arise from any anterior pituitary cell type and may be “clinically silent” or “totally silent.” Gonadotroph and null-cell adenomas are the most prevalent type of silent pituitary adenomas. Silent adenomas that are associated with neurologic defects require transsphenoidal surgery; radiation therapy may be used to treat residual or recurrent disease.
INTRODUCTION
Pituitary adenomas are uncommon. A cross-sectional study from the United Kingdom found that the prevalence of pituitary adenomas was 77.6 per 100,000 people.1 They can arise from any anterior pituitary cell type. Some pituitary adenomas cause clinical manifestations related to the excessive secretion of their hormonal products, whereas others are nonfunctioning or “silent” (Box 1). Although they are common among pituitary adenomas, the annual incidence of nonfunctioning pituitary adenomas is only approximately 1.5 per 100,000 people.2 TYPES OF SILENT PITUITARY ADENOMAS
Pituitary adenomas are classified based on the anterior pituitary cell type of origin (Table 1). Adenomas can therefore be lactotroph, somatotroph, corticotroph, gonadotroph and thyrotroph. Those that do not stain for any hormone by immunocytochemistry
Dr P.J. Snyder has been a consultant to Novartis and Pfizer, and has received research funding from Novartis. Dr S.E. Mayson is an investigator in the ACCESS trial (Novartis) and COR-2012-01. a Division of Endocrinology, The Warren Alpert Medical School, Brown University, 900 Warren Avenue, Suite 300, East Providence, RI 02914, USA; b Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, 12-135, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5160, USA * Corresponding author. E-mail address: [email protected] Endocrinol Metab Clin N Am - (2015) -–http://dx.doi.org/10.1016/j.ecl.2014.11.001 0889-8529/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
endo.theclinics.com
2
Mayson & Snyder
Box 1 Classification of pituitary adenomas based on the combination of immunocytochemistry, biochemical testing, and clinical findings Classic: Pituitary adenomas that secrete hormonal products in sufficient quantities to cause characteristic signs and symptoms related to the hormone excess. Subtle: Pituitary adenomas that secrete hormonal products that produce mild clinical manifestations related to the hormone excess. Clinically silent: Pituitary adenomas that can be classified by immunocytochemistry and secrete hormonal products that can be detected by biochemical testing but do not cause clinical signs or symptoms. Totally silent: Pituitary adenomas that can be classified by immunocytochemistry as arising from a specific anterior pituitary cell type but do not secrete a sufficient amount of their hormonal products to affect the serum concentration or urine excretion.
are called null cell, and those that stain for multiple hormones are called plurihormonal. Any type of pituitary adenoma can be silent, but a larger percentage of gonadotroph and null-cell adenomas and smaller percentage of lactotroph, somatotroph, and corticotroph are silent. Gonadotroph adenomas account for 25% to 35% of pituitary adenomas overall3–5 and 43% to 64% of silent adenomas.3,6 Null-cell adenomas are nearly as common.3 Clinically silent somatotroph adenomas account for up to 9%4 and clinically silent corticotroph adenomas 2.9% to 5.7% of pituitary adenomas in surgical series.7,8 Silent lactotroph adenomas occur in 1% to 2%3 and silent thyrotroph adenomas less than 1%.3,6,9 About 2% are plurihormonal.3 CLINICAL PRESENTATIONS
Silent pituitary adenomas are often detected as an incidental finding on MRI or when patients experience neurologic symptoms related to mass effect (Table 2). Pituitary hormone deficiencies occur in up to two-thirds10; however, in the authors’ experience, they are not usually the presenting findings. Progression of a nonfunctioning pituitary adenoma to one that is clinically apparent may occur. Several reports have described patients with known silent corticotroph adenomas who subsequently develop Cushing disease.8,11–13 Table 1 Types of silent pituitary adenomas based on immunocytochemistry Adenoma Type
Immunostaining
Null cell
None
Gonadotroph
FSH, LH, a-subunit
Thyrotroph
TSH
Corticotroph
ACTH
Somatotroph
GH
Lactotroph
Prolactin
Plurihormonal
Multiple hormones
Abbreviations: ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.
Silent Pituitary Adenomas
Table 2 Clinical presentations of silent pituitary adenomas Presenting Feature
Frequency
Incidental finding on MRI
7.9%–37.5%25,47
Neurologic symptoms Visual field deficits
60.8%14
Extraocular muscle palsy
14.2%14
Headaches
9.7%–60.8%10,14,47
Hormonal deficiencies GH
35.8%–61%10,14
LH/FSH
40%10,14
TSH
35.8%14
ACTH
32.7%14
Diabetes insipidus
1.9%10
Pituitary apoplexy
3.7%–9.6%14,47
Abbreviations: ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone. Data from Refs.10,14,25,47
DIAGNOSTIC EVALUATION
MRI is indicated to define both the size and extent of a silent pituitary adenoma. Extension into the sphenoid and cavernous sinuses can be seen in 14.2% to 16.9% and 19.2% to 33.2% of patients with nonfunctioning adenomas.10,14 Humphrey visual field testing is indicated when the mass extends into the suprasellar cistern and elevates the optic apparatus. All patients with nonfunctioning pituitary adenomas should undergo biochemical testing to evaluate for pituitary hormone excess. For those with clinically silent pituitary adenomas, biochemical testing can identify the mass as a pituitary adenoma and may identify the kind of adenoma by demonstrating excessive secretion of pituitary hormones. Gonadotroph Adenomas
In a patient with a clinically nonfunctioning sellar mass, a gonadotroph adenoma can be detected preoperatively by the in vivo hypersecretion of intact gonadotropins and/ or their subunits. In men with a sellar mass: An elevated follicle-stimulating hormone (FSH) associated with low testosterone and luteinizing hormone (LH) that is not elevated is diagnostic of a gonadotroph adenoma. An elevated serum FSH (with or without elevated alpha subunit) has been reported in up to one-quarter of patients with gonadotroph adenomas5,15,16; an isolated elevated alpha subunit concentration occurred in 7%.16 An elevated testosterone and LH, with or without an elevated FSH, is also diagnostic of a gonadotroph adenoma. An increase in LH beta subunit in response to synthetic thyrotropin-releasing hormone (TRH) is also diagnostic,17 but TRH is not available in the United States.
3
4
Mayson & Snyder
In women with a sellar mass: Premenopause, FSH hypersecretion by a gonadotroph adenoma can result in ovarian hyperstimulation. Clinical manifestations include oligomenorrhea or amenorrhea and large ovarian cysts. Biochemical testing will reveal elevated FSH, normal or low LH, and markedly elevated estradiol.18,19 After menopause, an elevated FSH concentration in the setting of a low or lownormal LH is highly suggestive of a gonadotroph adenoma. LH beta subunit response to synthetic TRH also occurs in women.20 Thyrotroph Adenomas
In a series of 63 patients with silent pituitary adenomas, 4 clinically euthyroid patients had staining for thyroid-stimulating hormone (TSH) b by immunocytochemistry and elevated serum TSH levels.15 Somatotroph Adenomas
Clinically silent somatotroph adenomas can be recognized preoperatively on the basis of an insulinlike growth factor 1 (IGF-1) concentration above the age-specific normal range. In a series of 100 consecutive patients with pituitary adenomas that were surgically excised, 24 had somatotroph adenomas immunocytochemically. Of these, 8, fully one-third, had an elevated IGF-1 concentration but no signs or symptoms of acromegaly and could therefore be considered to be clinically silent (Table 3).4 They were recognizable as somatotroph adenomas before surgery even though they resulted in not even subtle clinical manifestations of acromegaly. Corticotroph Adenomas
Preoperative testing also may help identify a sellar mass as a silent corticotroph adenoma before pathologic confirmation. Multiple microcysts are seen within the adenoma more often in patients with silent corticotroph adenomas than in those with adenomas causing Cushingoid features or other silent pituitary adenomas.21 In a retrospective series, patients who had silent corticotroph adenomas had significantly higher preoperative mean serum adrenocorticotropic hormone (ACTH) concentrations compared with null-cell adenomas (46 vs 19 ng/L; normal 5 5–27 ng/L), despite having similar serum cortisol levels.22 Another case series of 12 patients with silent corticotroph adenomas reported acute adrenal insufficiency in 2 patients after resection of their tumors, suggesting that they had secreted cortisol excessively preoperatively.23
Table 3 Distinguishing clinically silent and totally silent somatotroph adenomas from those that are subtle or classic Classification
Acromegalic Features
Serum IGF-1
GH Immunostaining
Classic
Typical
Elevated
Positive
Subtle
Mild
Elevated
Positive
Clinically silent
None
Elevated
Positive
Totally silent
None
Normal
Positive
Clinically silent adenomas cannot be recognized by a patient’s appearance but can be identified by an elevated serum insulinlike growth factor 1 (IGF-1) concentration. Adapted from Wade AN, Baccon J, Grady MS, et al. Clinically silent somatotroph adenomas are common. Eur J Endocrinol 2011;165(1):39–44.
Silent Pituitary Adenomas
MANAGEMENT
The management of a silent pituitary adenoma can include the following:
Observation Surgical resection Radiation therapy Medical therapy
Initial Treatment Observation
Close clinical and radiographic monitoring without specific treatment is an option for silent pituitary adenomas that are not causing neurologic symptoms. Case series of silent pituitary macroadenomas that are observed have reported clinical progression in 20% to 50% of subjects observed for 42 to 118 months.24–26 Because of high rates of progression, monitoring by MRI is essential when the patient is observed only. Surgery
Transsphenoidal surgery is the single best treatment option for silent pituitary adenomas that are causing neurologic compromise and could be considered for very large adenomas at risk for this complication. It is the only treatment that has a high likelihood of improving symptoms rapidly. In a study of 279 patients with visual deficits, vision improved in 50.6% and normalized in 39.4% after surgery.27 Although recovery of pituitary hormonal function may occur after surgery, a meta-analysis of 58 studies found that fewer than one-third of patients had postoperative improvement.28 The detection of hypopituitarism in a patient with a silent pituitary adenoma should prompt treatment with hormone replacement and not in itself be considered an indication for surgery. Complications after the transsphenoidal resection of a silent pituitary adenoma are similar to other pituitary macroadenomas. Postoperative complications may include the following:
New visual field deficits (3%)28 Cerebrospinal fluid leak or fistula formation (3%)28 Meningitis (1%)28 Blood loss requiring transfusion (
MD
a
, Peter J. Snyder,
MD
b,
*
KEYWORDS Nonfunctioning pituitary adenoma Silent pituitary adenoma Clinically silent pituitary adenoma KEY POINTS Nonfunctioning, or silent, pituitary adenomas can arise from any anterior pituitary cell type and may be “clinically silent” or “totally silent.” Gonadotroph and null-cell adenomas are the most prevalent type of silent pituitary adenomas. Silent adenomas that are associated with neurologic defects require transsphenoidal surgery; radiation therapy may be used to treat residual or recurrent disease.
INTRODUCTION
Pituitary adenomas are uncommon. A cross-sectional study from the United Kingdom found that the prevalence of pituitary adenomas was 77.6 per 100,000 people.1 They can arise from any anterior pituitary cell type. Some pituitary adenomas cause clinical manifestations related to the excessive secretion of their hormonal products, whereas others are nonfunctioning or “silent” (Box 1). Although they are common among pituitary adenomas, the annual incidence of nonfunctioning pituitary adenomas is only approximately 1.5 per 100,000 people.2 TYPES OF SILENT PITUITARY ADENOMAS
Pituitary adenomas are classified based on the anterior pituitary cell type of origin (Table 1). Adenomas can therefore be lactotroph, somatotroph, corticotroph, gonadotroph and thyrotroph. Those that do not stain for any hormone by immunocytochemistry
Dr P.J. Snyder has been a consultant to Novartis and Pfizer, and has received research funding from Novartis. Dr S.E. Mayson is an investigator in the ACCESS trial (Novartis) and COR-2012-01. a Division of Endocrinology, The Warren Alpert Medical School, Brown University, 900 Warren Avenue, Suite 300, East Providence, RI 02914, USA; b Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, 12-135, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5160, USA * Corresponding author. E-mail address: [email protected] Endocrinol Metab Clin N Am - (2015) -–http://dx.doi.org/10.1016/j.ecl.2014.11.001 0889-8529/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
endo.theclinics.com
2
Mayson & Snyder
Box 1 Classification of pituitary adenomas based on the combination of immunocytochemistry, biochemical testing, and clinical findings Classic: Pituitary adenomas that secrete hormonal products in sufficient quantities to cause characteristic signs and symptoms related to the hormone excess. Subtle: Pituitary adenomas that secrete hormonal products that produce mild clinical manifestations related to the hormone excess. Clinically silent: Pituitary adenomas that can be classified by immunocytochemistry and secrete hormonal products that can be detected by biochemical testing but do not cause clinical signs or symptoms. Totally silent: Pituitary adenomas that can be classified by immunocytochemistry as arising from a specific anterior pituitary cell type but do not secrete a sufficient amount of their hormonal products to affect the serum concentration or urine excretion.
are called null cell, and those that stain for multiple hormones are called plurihormonal. Any type of pituitary adenoma can be silent, but a larger percentage of gonadotroph and null-cell adenomas and smaller percentage of lactotroph, somatotroph, and corticotroph are silent. Gonadotroph adenomas account for 25% to 35% of pituitary adenomas overall3–5 and 43% to 64% of silent adenomas.3,6 Null-cell adenomas are nearly as common.3 Clinically silent somatotroph adenomas account for up to 9%4 and clinically silent corticotroph adenomas 2.9% to 5.7% of pituitary adenomas in surgical series.7,8 Silent lactotroph adenomas occur in 1% to 2%3 and silent thyrotroph adenomas less than 1%.3,6,9 About 2% are plurihormonal.3 CLINICAL PRESENTATIONS
Silent pituitary adenomas are often detected as an incidental finding on MRI or when patients experience neurologic symptoms related to mass effect (Table 2). Pituitary hormone deficiencies occur in up to two-thirds10; however, in the authors’ experience, they are not usually the presenting findings. Progression of a nonfunctioning pituitary adenoma to one that is clinically apparent may occur. Several reports have described patients with known silent corticotroph adenomas who subsequently develop Cushing disease.8,11–13 Table 1 Types of silent pituitary adenomas based on immunocytochemistry Adenoma Type
Immunostaining
Null cell
None
Gonadotroph
FSH, LH, a-subunit
Thyrotroph
TSH
Corticotroph
ACTH
Somatotroph
GH
Lactotroph
Prolactin
Plurihormonal
Multiple hormones
Abbreviations: ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.
Silent Pituitary Adenomas
Table 2 Clinical presentations of silent pituitary adenomas Presenting Feature
Frequency
Incidental finding on MRI
7.9%–37.5%25,47
Neurologic symptoms Visual field deficits
60.8%14
Extraocular muscle palsy
14.2%14
Headaches
9.7%–60.8%10,14,47
Hormonal deficiencies GH
35.8%–61%10,14
LH/FSH
40%10,14
TSH
35.8%14
ACTH
32.7%14
Diabetes insipidus
1.9%10
Pituitary apoplexy
3.7%–9.6%14,47
Abbreviations: ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone. Data from Refs.10,14,25,47
DIAGNOSTIC EVALUATION
MRI is indicated to define both the size and extent of a silent pituitary adenoma. Extension into the sphenoid and cavernous sinuses can be seen in 14.2% to 16.9% and 19.2% to 33.2% of patients with nonfunctioning adenomas.10,14 Humphrey visual field testing is indicated when the mass extends into the suprasellar cistern and elevates the optic apparatus. All patients with nonfunctioning pituitary adenomas should undergo biochemical testing to evaluate for pituitary hormone excess. For those with clinically silent pituitary adenomas, biochemical testing can identify the mass as a pituitary adenoma and may identify the kind of adenoma by demonstrating excessive secretion of pituitary hormones. Gonadotroph Adenomas
In a patient with a clinically nonfunctioning sellar mass, a gonadotroph adenoma can be detected preoperatively by the in vivo hypersecretion of intact gonadotropins and/ or their subunits. In men with a sellar mass: An elevated follicle-stimulating hormone (FSH) associated with low testosterone and luteinizing hormone (LH) that is not elevated is diagnostic of a gonadotroph adenoma. An elevated serum FSH (with or without elevated alpha subunit) has been reported in up to one-quarter of patients with gonadotroph adenomas5,15,16; an isolated elevated alpha subunit concentration occurred in 7%.16 An elevated testosterone and LH, with or without an elevated FSH, is also diagnostic of a gonadotroph adenoma. An increase in LH beta subunit in response to synthetic thyrotropin-releasing hormone (TRH) is also diagnostic,17 but TRH is not available in the United States.
3
4
Mayson & Snyder
In women with a sellar mass: Premenopause, FSH hypersecretion by a gonadotroph adenoma can result in ovarian hyperstimulation. Clinical manifestations include oligomenorrhea or amenorrhea and large ovarian cysts. Biochemical testing will reveal elevated FSH, normal or low LH, and markedly elevated estradiol.18,19 After menopause, an elevated FSH concentration in the setting of a low or lownormal LH is highly suggestive of a gonadotroph adenoma. LH beta subunit response to synthetic TRH also occurs in women.20 Thyrotroph Adenomas
In a series of 63 patients with silent pituitary adenomas, 4 clinically euthyroid patients had staining for thyroid-stimulating hormone (TSH) b by immunocytochemistry and elevated serum TSH levels.15 Somatotroph Adenomas
Clinically silent somatotroph adenomas can be recognized preoperatively on the basis of an insulinlike growth factor 1 (IGF-1) concentration above the age-specific normal range. In a series of 100 consecutive patients with pituitary adenomas that were surgically excised, 24 had somatotroph adenomas immunocytochemically. Of these, 8, fully one-third, had an elevated IGF-1 concentration but no signs or symptoms of acromegaly and could therefore be considered to be clinically silent (Table 3).4 They were recognizable as somatotroph adenomas before surgery even though they resulted in not even subtle clinical manifestations of acromegaly. Corticotroph Adenomas
Preoperative testing also may help identify a sellar mass as a silent corticotroph adenoma before pathologic confirmation. Multiple microcysts are seen within the adenoma more often in patients with silent corticotroph adenomas than in those with adenomas causing Cushingoid features or other silent pituitary adenomas.21 In a retrospective series, patients who had silent corticotroph adenomas had significantly higher preoperative mean serum adrenocorticotropic hormone (ACTH) concentrations compared with null-cell adenomas (46 vs 19 ng/L; normal 5 5–27 ng/L), despite having similar serum cortisol levels.22 Another case series of 12 patients with silent corticotroph adenomas reported acute adrenal insufficiency in 2 patients after resection of their tumors, suggesting that they had secreted cortisol excessively preoperatively.23
Table 3 Distinguishing clinically silent and totally silent somatotroph adenomas from those that are subtle or classic Classification
Acromegalic Features
Serum IGF-1
GH Immunostaining
Classic
Typical
Elevated
Positive
Subtle
Mild
Elevated
Positive
Clinically silent
None
Elevated
Positive
Totally silent
None
Normal
Positive
Clinically silent adenomas cannot be recognized by a patient’s appearance but can be identified by an elevated serum insulinlike growth factor 1 (IGF-1) concentration. Adapted from Wade AN, Baccon J, Grady MS, et al. Clinically silent somatotroph adenomas are common. Eur J Endocrinol 2011;165(1):39–44.
Silent Pituitary Adenomas
MANAGEMENT
The management of a silent pituitary adenoma can include the following:
Observation Surgical resection Radiation therapy Medical therapy
Initial Treatment Observation
Close clinical and radiographic monitoring without specific treatment is an option for silent pituitary adenomas that are not causing neurologic symptoms. Case series of silent pituitary macroadenomas that are observed have reported clinical progression in 20% to 50% of subjects observed for 42 to 118 months.24–26 Because of high rates of progression, monitoring by MRI is essential when the patient is observed only. Surgery
Transsphenoidal surgery is the single best treatment option for silent pituitary adenomas that are causing neurologic compromise and could be considered for very large adenomas at risk for this complication. It is the only treatment that has a high likelihood of improving symptoms rapidly. In a study of 279 patients with visual deficits, vision improved in 50.6% and normalized in 39.4% after surgery.27 Although recovery of pituitary hormonal function may occur after surgery, a meta-analysis of 58 studies found that fewer than one-third of patients had postoperative improvement.28 The detection of hypopituitarism in a patient with a silent pituitary adenoma should prompt treatment with hormone replacement and not in itself be considered an indication for surgery. Complications after the transsphenoidal resection of a silent pituitary adenoma are similar to other pituitary macroadenomas. Postoperative complications may include the following:
New visual field deficits (3%)28 Cerebrospinal fluid leak or fistula formation (3%)28 Meningitis (1%)28 Blood loss requiring transfusion (
