Pituitary Tumors and Incidentalomas Bijan Ahrari, MD, FACE, ECNU Palm Medical Group
Background Pituitary incidentaloma: a previously unsuspected pituitary lesion that is discovered on an imaging study performed for an unrelated reason Microadenoma <1cm Macroadenoma > or equal to 1cm Sellar/Parasellar Mass Pituitary Adenoma
Prevalence of Pituitary Adenomas Adenomas 77.6 per 100,000 population Lactotroph adenomas 44.4 Nonfunctioning adenomas 22.2 Somatotroph adenomas 8.6 Corticotroph adenomas 1.2 In combined autopsy data, the average frequency of a pituitary adenoma was 10.6% Imaging: microincidentalomas were seen on MRI in 10 38% of patients.
Etiology of Incidentalomas 91% are pituitary adenomas 48% functional 43% non-functional 9% are non-pituitary Rathke s cleft cyst Craniopharyngioma Chrodoma Mets Endocrinol Metab Clin N Am 1999;28:81
Endocrinol Metab Clin N Am 2008;37:151
Evaluation of a Pituitary Incidentaloma
Initial Evaluation We recommend that patients presenting with a pituitary incidentaloma undergo a complete history and physical examination that includes evaluations for evidence of hypopituitarism and a hormone hypersecretion syndrome. Patients with evidence of either of these conditions should undergo an appropriately directed biochemical evaluation
Should We Evaluate for Hypersecretion? We recommend that all patients with a pituitary incidentaloma, including those without symptoms, undergo clinical and laboratory evaluations for hormone hypersecretion Level of evidence: moderate quality Rationale: likelihood of finding a hormonally active incidentaloma is low, however, early detection and therapy is likely to reduce morbidity
Evaluation for Hypersecretion Data on the prevalence of hormone hypersecretion in incidentalomas is limited Small retrospective observational studies Estimated from autopsy data Data is weak in regards to the pros/cons of pursuing a limited vs. detailed screening strategy Guideline task force was divided on this issue Assessment should include evaluation of prolactin, IGF-1, and an assessment of ACTH hypersecretion
Prolactin Hypersecretion Data is strongest for the importance of screening for hyperprolactinemia Pooled data shows overall prevalence of prolactin hypersecretion in incidental pituitary adenomas to be 13.4% 1,2,3 11.9% in microadenomas alone 1 12.5% in macroadenomas alone 2 15.2% in combined micro/macro adenomas 3 During prospective follow up no patients developed hyperprolactinemia after having an initial negative screen 3 1 Clin Endocrinol (Oxf) 1999;51:109 2 Pituitary 2004;7:145 3 Arch Intern Med 1995;155:181
Diagnosis of Hyperprolactinemia To establish the diagnosis of hyperprolactinemia, we recommend a single measurement of serum prolactin; a level above the upper limit of normal confirms the diagnosis as long as the serum sample was obtained without excessive venipuncture stress. We recommend against dynamic testing of prolactin secretion for the diagnosis of hyperprolactinemia. A prolactin level greater than 500 mcg/liter is diagnostic of a macroprolactinoma. Although a prolactin level greater than 250 mcg/liter usually indicates the presence of a prolactinoma, selected drugs, including risperidone and metoclopramide, may cause prolactin elevations above Even minimal prolactin elevations may be consistent with the presence of a prolactinoma, but a non-prolactin-secreting mass should first be considered
Diagnosis of Hyperprolactinemia In patients with asymptomatic hyperprolactinemia, we suggest assessing for macroprolactin. The term macroprolactinemia denotes the situation in which a preponderance of the circulating prolactin consists of larger molecules: dimeric and polymeric prolactin. Macroprolactin is less bioactive and less likely to cause symptoms, however clinical disease does occur. Galactorrhea is present in 20%, oligo/amenorrhea in 45%, and pituitary adenomas in 20%.
Diagnosis of Hyperprolactinemia When there is a discrepancy between a very large pituitary tumor and a mildly elevated prolactin level, we recommend serial dilution of serum samples to eliminate an artifact that can occur with some immunoradiometric assays leading to a falsely low prolactin value ( hook effect ) Expert Consult online
Causes of hyperprolactinemia We recommend excluding medication use, renal failure, hypothyroidism, and parasellar tumors in patients with symptomatic nonphysiological hyperprolactinemia. A number of physiological states including pregnancy, breast-feeding, stress, exercise, and sleep can cause prolactin elevation, as can medications. Because prolactin secretion is tonically inhibited by hypothalamic dopamine, disruption or compression of the pituitary stalk by a non-prolactin-secreting pituitary tumor or other parasellar mass will lead to hyperprolactinemia.
Stalk Effect vs. Prolactinoma Expert Consult Online
GH Hypersecretion Silent GH-secreting tumors are rare and data is limited on the prevalence of subclinical GH hypersecretion in incidentalomas Prospective observation study of 18 pituitary incidentalomas 1 1/18 (5.6%) was GH secreting (macroadenoma) 1 JAMA 1990;263:2772
ACTH Hypersecretion Prevalence in pituitary incidentalomas is not known No study has systematically screened incidentalomas for subclinical glucorticoid excess Recommendation for screening is based on data in patients with adrenal incidentalomas and subclinical Cushing s who benefit from detection and treatment in terms of co-morbid diabetes, HTN, obesity, and osteoporosis Appropriate screening tests: 1mg DST, 24hr urine free cortisol, MN salivary cortisol Many only screening if clinical symptoms are present
Immunohistochemical Data Autopsy series of 3,048 consecutive cases identified 334 pituitary adenomas in 316 pituitary glands 39.5% stained for prolactin 13.8% for ACTH 1.8% for GH Staining characteristics do not necessarily equate to clinically relevant elevations of circulating hormones Eur J Endocrinol Metab 2006;91:4769
Immunohistochemical Data Eur J Endocrinol Metab 2006;91:4769
Should We Evaluate for Hypopituitarism? We recommend that patients with a pituitary incidentaloma with or without symptoms also undergo clinical and laboratory evaluations for hypopituitarism Level of evidence: moderate Data from small observational studies of combined micro/macroadenomas shows a modest prevalence of hypopituitarism in pituitary incidentalomas 7/66 patients (10.6%) 1 19/46 patients (41.3%) 2 1 J Neurosurg 2006;104:884 2 Pituitary 2004;7:145
Does Size Matter? Observational studies show low rates of hypopituitarism in microadenomas 0/31 patients 1 0/15 patients 2 0/7 patients 3 19/38 patients with micoradenomas and nml IGF-1 shown to fail GHRH/Arginine stim test (industry funded) 4 Task force more strongly favored screening for hypopituitarism in macroadenomas and larger microadenomas (6-9mm) but not necessarily in smaller microincidentalomas Evaluation of larger microadenomas is based on expert opinion/experience and no specific data in evaluating hypotiuitarism in small (<6mm) vs. large (6-9mm) incidentalomas exists 1 Clin Endocrinol (Oxf) 1999;51:109 2 Arch Intern Med 1995;155:181 3 JAMA 1990;263:2772 4 Clin Endocrinol (Oxf) 2008;69:292
What Deficits Should We Test For? Pooled hormonal deficiencies across studies (micro/macroadenomas) Gonadotropin deficiency up to 30% Thyroid axis deficiency up to 28% ACTH-cortisol axis deficiency up to 18% GH-IGF-1 axis deficiency up to 8% The recommended screening for all incidentalomas is debated Minimal: FT4, AM cortisol, testosterone (men) More complete: IGF-1, LH/FSH/Testosterone, TSH/FT4, AM cortisol Confirmatory stimulatory testing of the pituitary- adrenal or GH- IGF-1 axis should be performed if baseline testing suggests hypopituitarism
Should We Screen for Other Mass Effects? We recommend that all patients presenting with a pituitary incidentaloma abutting the optic nerves or chiasm on magnetic resonance imaging (MRI) undergo a formal visual field (VF) examination Level of evidence: high quality When an incidentaloma abuts the nerves or chiasm baseline visual field assessment should be obtained regardless of mass size or the presence or absence of visual symptoms
Occult Visual Field Deficits Prospective observational study of 67 incidentally discovered pituitary adenomas 1 3/67 (4.5%) of patients had unrecognized visual field deficits on formal testing in All were macroadenomas Other studies show undetected rates of visual field defects as high as 15% 2 1 Clin Endocrinol (Oxf) 1999;51:109 2 J Clin Endocrinol Metab 2002;87:4869 -?
How Best to Image Pituitary Incidentalomas All patients should have a MRI scan, if possible, to evaluate the pituitary incidentaloma (if the incidentaloma was initially only diagnosed by CT scan) to better delineate the nature and extent of the incidentaloma Level of evidence: high quality MRI should use a pituitary protocol with fine cuts through the sella with and without gadolinium contrast
Follow up of Pituitary Incidentalomas
Should We Repeat Imaging? MRI scan of the pituitary 6 months after the initial scan if the incidentaloma is a macroincidentaloma and 1 yr after the initial scan if it is a microincidentaloma Level of evidence: low quality In patients whose incidentaloma does not change in size, we suggest repeating the MRI every year for macroincidentalomas and every 1 2 yr in microincidentalomas for the following 3 yrs and gradually less frequently thereafter Level of evidence: low quality
Data on Incidentaloma Growth Meta-analysis of prospective studies evaluating the natural history of non-functional pituitary incidentalomas 1 8.2% enlarged over 472 person-years of follow up For microincidentalomas pooled data from 8 prospective observational studies showed 17/160 patients (10.6%) enlarged over 2-7 years of follow-up Meta-analysis data shows enlargement rate of 1.7%/year 1 For macroadenomas pooled data of data from 10 prospective observational studies showed 85/353 patients (24%) enlarged 28/353 patients (8%) developed visual field abnormality 7/353 patients (2%) developed apoplexy 1 J Clin Endocrinol Metab 2011; 96:905
Imaging Follow Up Rationale for repeat MRI during the first year of follow up in all pituitary incidentalomas Some tumors enlarge and the true proliferative nature of incidentalomas is unknown Guideline for MRI follow up of pituitary incidentalomas Based on expert opinion Derived from various algorithms proposed in prior studies varied and none have been validated Subsequent imaging is obtained gradually less frequently During first 3 years (q12months for macroadenomas, q12-24 months for microadenomas) Then every other year of the next 6 years, or every five years (debated)
When Are Repeat VFs Appropriate? VF testing in patients with a pituitary incidentaloma that enlarges to abut or compress the optic nerves or chiasm on a follow-up imaging study Level of evidence: high quality We suggest that clinicians do not need to test VF in patients whose incidentalomas are not close to the chiasm and who have no new symptoms and are being followed closely by MRI Level of evidence: very low quality Guidelines are unclear as to the specific data leading to these recommendations
Should We Repeat Hormonal Evaluation? Clinical and biochemical evaluations for hypopituitarism 6 months after the initial testing and yearly thereafter in patients with a pituitary macro-incidentaloma, although typically hypopituitarism develops with the finding of an increase in size of the incidentaloma Level of evidence: low quality Rationale for recommendation: high risk of untreated hypopituitarism outweighs the paucity of data
Data for New Pituitary Dysfunction Meta-analysis of prospective studies evaluating non-functional pituitary incidentalomas 1 New endocrine dysfunction in 2.4%/year For macroadenomas pooled data from 4 prospective observational studies showed new hypofunction in 1/7 patients (14.3%) and 3/28 patients (10.7%) all occurred in the setting of tumor enlargement 4/37 patients (10.8%) and 3/28 patients (10.7%) due to pituitary apoplexy Unclear how often new dysfunction develops in the absence of tumor growth or apoplexy Rapid growth may increase the risk of new hypopituitarism 1 J Clin Endocrinol Metab 2011; 96:905
What About Hormonal Evaluation in Microindentalomas? We suggest that clinicians do not need to test for hypopituitarism in patients with pituitary microincidentalomas whose clinical picture, history, and MRI do not change over time Level of evidence: low quality Pooled data from 6 observational studies showed no changes in pituitary function in microincidentalomas during follow-up
Follow-up Patients who develop any signs or symptoms potentially related to the incidentaloma or who show an increase in size of the incidentaloma on MRI should undergo more frequent or detailed evaluations as indicated clinically Level of evidence: low quality No studies cited in the guidelines to substantiate this recommendation
Indications for Surgical Therapy
What are the Indications for Surgery? We recommend that patients with a pituitary incidentaloma be referred for surgery if they have the following: A VF deficit due to the lesion Other visual abnormalities, such as opthalmoplegia or neurological compromise due to compression by the lesion Lesion abutting or compromising the optic nerve or chiasm on MRI Pituitary apoplexy with visual disturbance Hypersecreting tumors other than prolactinomas as recommended by other guidelines of The Endocrine Society and the Pituitary Society Level of evidence: high quality Rationale for recommendation: Task force emphasis on alleviating or preventing visual or neurologic compromise rather than potential surgical morbidities (DI, post-op hypopituitarism, cost)
Summary of Evidence Substantial evidence supports the recommendation for surgery in pituitary incidentalomas causing visual or neurologic compromise The risks/benefits of performing surgery in pituitary incidentalomas abutting or in close proximity to the optic chiasm but not causing VF deficits has not been quantified Expert option suggests surgery in these situations given the risk of potential future vision disturbances Benefits of surgery on preventing future VF abnormalities is not known Other guidelines for the management of hypersecretory pituitary adenomas (other than prolactinomas) support surgery for functional tumors
Evidence in Apoplexy Surgery is indicated when apoplexy is accompanied by visual disturbances In the absence of visual symptoms, a retrospective review of 30 cases of pituitary apoplexy showed similar rates of long term hypopituitarism in patients managed conservatively (imaging and hormonal testing follow up) vs. those who were treated surgically 1 1 Br J Neurosurg 2006; 20:379
Additional Considerations When Recommending Surgery Patient age Young patients have a higher lifetime probability of tumor enlargement Older patients have a higher risk of surgical complications Patient s desire for future fertility The success of the surgery is highly dependent on the availability of skilled neurosurgeons
Are There Other Situations in which to Consider Surgery? We suggest that surgery be considered for patients with a pituitary incidentaloma if they have the following Clinically significant growth of the pituitary incidentaloma Loss of endocrinological function A lesion close to the optic chiasm and a plan to become pregnant Unremitting headache Level of evidence: low quality
Regarding Tumor Growth There are no size cut-offs for growth that necessitate surgery Clinically significant growth is growth that could pose a health risk to the patient (such as to their vision) Location and growth characteristics are the most important i.e. rapid (within 1-2 years), or toward the chiasm Incidentalomas that have shown the propensity for growth tend to continue to grow Surgery is most effective when lesions are small
Surgery to Improve Hypopituitarism Some data from surgical series of symptomatic patients show that pituitary function can improve with surgery 1,2 One series of 26 large non-functional adenomas showed recovery in a significant number of patients by 2-3 months post-op 2 4/26 GH deficient patients (15% recovery) 8/25 hypogonadal patients (32% recovery) 12/21 hypothyroid patients (57% recovery) 6/16 adrenal insufficient patients (38% recovery) It is not clear whether the benefits seen in these symptomatic patients with macroadenomas can be extrapolated to asymptomatic incidentalomas with hormonal deficiencies 1 J Clin Endocrinol Metab 1994;79:348 2 J Clin EndocrinolMetab 1986;62: 1173
Other Relative Indications for Surgery Patients planning pregnancy who have tumors close to the optic chiasm Due to the small risk of lactotroph hyerplasia in pregnancy leading to tumor compression of the optic chiasm Headache may or may not improve with transphenoidal removal of the tumor