Pituitary Incidentaloma: An Endocrine Society Clinical Practice Guideline Incidentaloma Guide 2011

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Pituitary Incidentaloma: An Endocrine Society Clinical

Practice Guideline

Pamela U. Freda, Albert M. Beckers, Laurence Katznelson, Mark E. Molitch,

Victor M. Montori, Kalmon D. Post, and Mary Lee Vance

Columbia College of Physicians & Surgeons (P.U.F.), New York, New York 10032; Centre Hospitalier

Universitaire de Lie` ge (A.M.B.), University of Lie` ge Domaine Universitaire du Sart-Tilman, 4020 Lie` ge,

Belgium; Stanford University (L.K.) Stanford, California 94305; Northwestern University Feinberg School

of Medicine (M.E.M.) Chicago, Illinois 60611; Mayo Clinic Rochester (V.M.M.), Rochester, Minnesota

55905; Mount Sinai Medical Center (K.D.P.) New York, New York 10029; and University of Virginia

Health Science Center (M.L.V.) Charlottesville, Virginia 22903

Objective: The aim was to formulate practice guidelines for endocrine evaluation and treatment

of pituitary incidentalomas.

Consensus Process: Consensus was guided by systematic reviews of evidence and discussions

through a series of conference calls and e-mails and one in-person meeting.

Conclusions: We recommend that patients with a pituitary incidentaloma undergo a complete

history and physical examination, laboratory evaluations screening for hormone hypersecretion

and for hypopituitarism, and a visual field examination if the lesion abuts the optic nerves or

chiasm. We recommend that patients with incidentalomas not meeting criteria for surgical removal

be followed with clinical assessments, neuroimaging (magnetic resonance imaging at 6 months for

macroincidentalomas, 1 yr for a microincidentaloma, and thereafter progressively less frequently

if unchanged in size), visual field examinations for incidentalomas that abut or compress the optic

nerve and chiasm (6 months and yearly), and endocrine testing for macroincidentalomas (6 months

and yearly) after the initial evaluations. We recommend that patients with a pituitary inci-

dentaloma be referred for surgery if they have a visual field deficit; signs of compression by the

tumor leading to other visual abnormalities, such as ophthalmoplegia, or neurological com-

promise due to compression by the lesion; a lesion abutting the optic nerves or chiasm; pituitary

apoplexy with visual disturbance; or if the incidentaloma is a hypersecreting tumor other than

a prolactinoma. (J Clin Endocrinol Metab 96: 894–904, 2011)

Summary of Recommendations

1.0 Initial evaluation of a patient with a pituitary

incidentaloma

1.1 We recommend that patients presenting with a pi-

tuitary incidentaloma undergo a complete history and

physical examination that includes evaluations for evi-

dence of hypopituitarism and a hormone hypersecretion

syndrome. Patients with evidence of either of these con-

ditions should undergo an appropriately directed bio-

chemical evaluation:

1.1.1 We recommend that all patients with a pituitary

incidentaloma, including those without symptoms, un-

dergo clinical and laboratory evaluations for hormone hy-

persecretion (1ⱍQQQE).

1.1.2 We recommend that patients with a pituitary inci-

dentaloma with or without symptoms also undergo clinical

and laboratory evaluations for hypopituitarism (1ⱍQQQE).

1.1.3 We recommend that all patients presenting with

a pituitary incidentaloma abutting the optic nerves or chi-

asm on magnetic resonance imaging (MRI) undergo a for-

mal visual field (VF) examination (1ⱍQQQQ).

ISSN Print 0021-972X ISSN Online 1945-7197

Printed in U.S.A.

doi: 10.1210/jc.2010-1048 Received May 6, 2010. Accepted December 7, 2010.

For editorial see page 939

Abbreviations: CT, Computed tomography; GHD, GH deficiency; MRI, magnetic resonance

imaging; VF, visual field.

SPECIAL FEATURE

Clinical Practice Guideline

894 jcem.endojournals.org J Clin Endocrinol Metab, April 2011, 96(4):894–904

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1.1.4 We recommend that all patients have a MRI scan,

if possible, to evaluate the pituitary incidentaloma [if the

incidentaloma was initially only diagnosed by computed

tomography (CT) scan] to better delineate the nature and

extent of the incidentaloma (1ⱍQQQQ).

2.0 Follow-up testing of the pituitary

incidentaloma

2.1 Patients with incidentalomas who do not meet cri-

teria for surgical removal of the tumor should receive non-

surgical follow-up (2ⱍQQEE) with clinical assessments

and the following tests:

2.1.1 MRI scan of the pituitary 6 months after the ini-

tial scan if the incidentaloma is a macroincidentaloma and

1 yr after the initial scan if it is a microincidentaloma

(1ⱍQQEE). In patients whose incidentaloma does not

change in size, we suggest repeating the MRI every year for

macroincidentalomas and every 1–2 yr in microinciden-

talomas for the following 3 yr, and gradually less fre-

quently thereafter (2ⱍQQEE).

2.1.2 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 (1ⱍQQQQ). We suggest that

clinicians do not need to test VF in patients whose inciden-

talomas are not close to the chiasm and who have no new

symptoms and are being followed closely by MRI

(2ⱍQEEE).

2.1.3 Clinical and biochemical evaluations for hypop-

ituitarism 6 months after the initial testing and yearly

thereafter in patients with a pituitary macroincidenta-

loma, although typically hypopituitarism develops with

the finding of an increase in size of the incidentaloma

(1ⱍQQEE). We suggest that clinicians do not need to test

for hypopituitarism in patients with pituitary microinci-

dentalomas whose clinical picture, history, and MRI do

not change over time (2ⱍQQEE).

2.2 Patients who develop any signs or symptoms po-

tentially related to the incidentaloma or who show an in-

crease in size of the incidentaloma on MRI should undergo

more frequent or detailed evaluations as indicated clini-

cally (1ⱍQQEE).

3.0 Indications for surgical therapy of the pituitary

incidentaloma

3.1 We recommend that patients with a pituitary inci-

dentaloma be referred for surgery if they have the follow-

ing (1ⱍQQQQ):

•A VF deficit due to the lesion.

•Other visual abnormalities, such as ophthalmoplegia

or neurological compromise due to compression by

the lesion.

•Lesion abutting or compressing the optic nerves 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.

3.2 We suggest that surgery be considered for patients

with a pituitary incidentaloma if they have the following

(2ⱍQQEE):

•Clinically significant growth of the pituitary

incidentaloma.

•Loss of endocrinological function.

•A lesion close to the optic chiasm and a plan to be-

come pregnant.

•Unremitting headache.

Method of Development of Evidence-

Based Clinical Practice Guidelines

The Clinical Guidelines Subcommittee of The Endocrine

Society deemed the subject of pituitary incidentalomas a

priority area in need of practice guidelines and appointed

a Task Force to formulate evidence-based recommenda-

tions. Consensus was guided by systematic reviews of ev-

idence and discussions through a series of conference calls

and e-mails and one in-person meeting. An initial draft

guideline was prepared by the Task Force, with the help of

a medical writer, and reviewed and commented on by

members of The Endocrine Society and the European So-

ciety of Endocrinology. A second draft was reviewed and

approved by The Endocrine Society Council. At each stage

of review, the Task Force received written comments and

incorporated substantive changes. The evidence was de-

veloped using the Grading of Recommendations, Assess-

ment, Development, and Evaluation (GRADE) system to

describe the strength of recommendations and the quality

of evidence, which was low or very low. The GRADE

group is an international group with expertise in devel-

opment and implementation of evidence-based guidelines

(1). A detailed description of the grading scheme has been

published elsewhere (2). The Task Force used the best

available research evidence identified and one commis-

sioned systematic review to develop some of the recom-

mendations (3). The Task Force also used consistent lan-

guage and graphical descriptions of both the strength of a

recommendation and the quality of evidence. In terms of

the strength of the recommendation, strong recommen-

dations use the phrase “we recommend” and the number

1, and weak recommendations use the phrase “we sug-

gest” and the number 2. Cross-filled circles indicate the

quality of the evidence, such that QEEE denotes very low

J Clin Endocrinol Metab, April 2011, 96(4):894–904 jcem.endojournals.org 895

quality evidence; QQEE, low quality; QQQE, moderate

quality; and QQQQ, high quality. The final category may

include circumstances in which there is a consistent ob-

servation of uniformly poor serious outcomes that will not

reverse spontaneously, but when treated, often through

surgical means, may dramatically improve or be cured.

The Task Force has confidence that persons who receive

care according to the strong recommendations will derive,

on average, more good than harm. Weak recommenda-

tions require more careful consideration of the person’s

circumstances, values, and preferences to determine the

best course of action. Linked to each recommendation is

a description of the evidence and the values that panelists

considered in making the recommendation; in some in-

stances, there are remarks, a section in which panelists

offer technical suggestions for testing conditions, dosing,

and monitoring. These technical comments reflect the

best available evidence applied to a typical person being

treated. Often this evidence comes from the unsystem-

atic observations of the panelists and their values and

preferences; therefore, these remarks should be consid-

ered suggestions.

Definition, etiology, and epidemiology of pituitary

incidentalomas

Definition of pituitary incidentaloma

A pituitary incidentaloma is a previously unsuspected

pituitary lesion that is discovered on an imaging study

performed for an unrelated reason. By definition, the im-

aging study is not done for a symptom specifically related

to the lesion, such as visual loss, or a clinical manifestation

of hypopituitarism or hormone excess, but rather for the

evaluation of symptoms such as headache, or other head

or neck neurological or central nervous system complaints

or head trauma (4–9). Studies reviewed for these guide-

lines vary, however, in their definition of a “pituitary in-

cidentaloma.” For example, some studies exclude cystic

lesions and include only those that fulfill radiographic

criteria for a pituitary adenoma (4, 5), whereas others

include all lesions (6–9). The guidelines presented here

are relevant to all pituitary incidentalomas, those that

have the appearance typical of a pituitary adenoma as

well as cystic lesions. By convention, microincidenta-

lomas are less than 1 cm and macroincidentalomas are

at least 1 cm in size.

Etiology of pituitary incidentalomas

Because incidentalomas infrequently come to surgery,

the true pathological diagnoses of most are unknown. In

a series of sellar masses that required surgery, 91% were

pituitary adenomas and about 9% were nonpituitary in

origin, of which most were craniopharyngiomas and

Rathke’s cleft cysts (10). It is unknown whether the

etiologies of incidentalomas are similar to this surgical

cohort, but in one series of 29 incidentalomas that did

come to surgery, 23 were found to be pituitary adeno-

mas, four were Rathke’s cleft cysts, and two were cra-

niopharyngiomas (6, 7, 9). Immunohistochemical anal-

ysis of 20 of these adenomas was reported as negative in

50%, plurihormonal in 20%, gonadotroph positive in

15%, and GH positive in 10% (6, 7, 9). In another series

of 139 mass lesions without overt symptoms, 73 had a

cystic appearance on imaging study (5). Cystic lesions

are most likely to be Rathke’s cleft cysts, which often

present incidentally, or craniopharyngiomas (11, 12).

Of the non-cystic-appearing incidentalomas, nearly all

are likely to be pituitary adenomas, and most clinically

nonfunctioning pituitary adenomas are of gonadotrope

origin as determined by immunocytochemical studies

(13–15). However, the differential diagnosis of sellar

incidentalomas is broad and should include other pos-

sibilities (10).

Epidemiology of pituitary incidentalomas

The prevalence of pituitary incidentalomas has been

estimated from data on pituitary adenomas found at au-

topsy and from imaging in patients who underwent a CT

or MRI of the head for reasons other than pituitary dis-

ease. Because most pituitary incidentalomas are adeno-

mas, autopsy data on adenomas may provide information

relevant to incidentaloma detected during life. In com-

bined autopsy data, the average frequency of a pituitary

adenoma was 10.6% (16). The tumors were distributed

equally across genders and the adult age range, and nearly

all of these incidentalomas were microadenomas (16). In

adults who underwent cranial imaging studies for reasons

other than pituitary disease, microincidentalomas were

seen on CT in 4–20% (17–19) or on MRI in 10–38% (20)

of patients. Macroincidentalomas were found in 0.2% of

patients who underwent CT scans for central nervous sys-

tem symptoms (21) and by MRI in 0.16% of a population

study cohort (22). In pooled data from 10 series of pitu-

itary incidentalomas, 160 of 353 (45%) were macroinci-

dentalomas (4–9, 23–26), a larger percentage than has

been found on autopsy studies and the other screening

studies. This suggests that these patients may in fact have

had some symptom that was not readily apparent or re-

ported but that led to the imaging study or that microin-

cidentalomas were not referred to these centers for

evaluation.

Data are not available on pituitary incidentalomas in

the pediatric population; these guidelines are limited to

adults.

896 Freda et al. Guidelines on Pituitary Incidentaloma J Clin Endocrinol Metab, April 2011, 96(4):894–904

1.0 Initial evaluation of a patient with a pituitary

incidentaloma

Recommendations

1.1 We recommend that patients presenting with a pi-

tuitary incidentaloma undergo a complete history and

physical examination that includes evaluations for evi-

dence of hypopituitarism and a hormone hypersecretion

syndrome. Patients with evidence of either of these con-

ditions should undergo an appropriately directed bio-

chemical evaluation.

1.1.1 We recommend that all patients with a pituitary

incidentaloma, including those without symptoms, un-

dergo clinical and laboratory evaluations for hormone hy-

persecretion (1ⱍQQQE).

1.1–1.1.1 Evidence

The goals of the endocrine evaluation of pituitary in-

cidentalomas are to identify hormone hypersecretion and

hypopituitarism. The recommendations for evaluation of

pituitary function considered the likelihood of an abnor-

mality in a given patient. However, valid estimates of the

pretest probability of an abnormal test of pituitary func-

tion could not be definitively determined because litera-

ture on this topic is sparse. Therefore, recommendations

for the evaluation relied heavily on clinical experience.

Data on the prevalence of hormone hypersecretion in

patients with an incidentaloma are available from small

observational studies (most retrospective) and estimated

from autopsy data. Screening for hypersecretion is impor-

tant to perform because the prevalence of clinically evident

pituitary adenomas has recently been appreciated to be as

high as 1/1000 in a Belgian population (27), and 0.776/

1000 (of which 0.542/1000 were hormone secreting) in a

region of the United Kingdom (28), or as low as 0.04/1000

in Finland (29). The incidence of incidentally discovered

pituitary adenomas was recently reported as 0.016/1000

in a retrospective review from Finland (29).

The evaluation for hypersecretion should include an

assessment for prolactin, GH, and ACTH hypersecretion.

Evidence is strongest for the need to measure a serum pro-

lactin level in all patients presenting with an incidenta-

loma. Ideally, for patients with large macroincidentalo-

mas, the laboratory should measure prolactin levels in

diluted serum to ensure that levels are not falsely lowered

by a hook effect in the assay. Hyperprolactinemia was

found in five of 42 patients with microincidentalomas at

initial evaluation (4), but in other studies none of 22 de-

veloped a prolactin elevation on prospective follow-up (8,

9). In other studies, prolactinomas were detected in seven

of 46 patients with incidentalomas (micro and macro com-

bined) (7). In macroincidentalomas, prolactin levels were

elevated in two of 16 (9). In a large autopsy study, 39.5%

of the adenomas detected (most microadenomas) were

found to stain positive for prolactin (30). These data might

suggest that prolactinomas are very common among pi-

tuitary incidentalomas, which is contrary to the literature.

Autopsy data should cautiously be considered represen-

tative of incidentalomas presenting in life because the au-

topsy studies lack clinical data, and prolactin staining may

not have been associated with clinically relevant circulat-

ing hyperprolactinemia. Patients with hyperprolactinemia

could receive a trial of dopamine agonist therapy so long

as it is recognized that mild/moderate elevations may be

due to stalk compression from a lesion other than a pro-

lactinoma. In these patients, tumor shrinkage is unlikely,

and growth of the incidentaloma is still possible, so con-

tinued follow-up with repeat imaging is warranted. The

treatment of hyperprolactinemia has been recently re-

viewed (31).

Although silent somatotroph-secreting tumors are rare,

evaluation for the possibility is recommended. In a pro-

spective study, one of 11 macroincidentalomas were

found to have an elevated IGF-I consistent with subclinical

GH excess (8), and in another study, two of 13 inciden-

talomas that were surgically removed were positive on

immunohistochemistry for GH (7). One series of 3048

autopsies reported 334 pituitary adenomas, of which

1.8% stained positive for GH (30). Because the initial

treatment for a GH-secreting tumor is surgery and GH-

secreting microadenomas can be cured surgically in almost

all cases, screening for a GH-secreting tumor by measure-

ment of an IGF-I level is warranted. If this is elevated,

further evaluation for GH excess is suggested.

Screening for glucocorticoid excess due to a possible

corticotroph tumor may also be considered when this is

suspected clinically. In the series of 3048 autopsies, 13.8%

of 334 pituitary adenomas stained positive for ACTH

(30). No systematic screening of incidentalomas for sub-

clinical glucocorticoid excess has been reported (8, 9).

However, patients with adrenal incidentalomas may have

Cushing’s syndrome-associated morbidities such as dia-

betes mellitus, hypertension, obesity, and osteoporosis

(32), so in a patient with a pituitary incidentaloma sub-

clinical Cushing’s disease could also be associated with

these morbidities (16). In patients with a clinical suspicion

for glucocorticoid excess, laboratory screening is there-

fore suggested. Detection of subclinical hypercortisolism

should be followed by evaluation for possible Cushing’s

disease. The screening and evaluation of Cushing’s dis-

ease has been reviewed in the “Diagnosis of Cushing’s

Syndrome: an Endocrine Society Clinical Practice

Guideline” (33).

The Task Force does not recommend the routine mea-

surement of plasma ACTH levels in patients with inciden-

J Clin Endocrinol Metab, April 2011, 96(4):894–904 jcem.endojournals.org 897

talomas. However, some of the Task Force members often

measure ACTH because a small percentage of inciden-

talomas may be silent corticotroph tumors (34), and

occasionally plasma ACTH levels are elevated in pa-

tients harboring these tumors despite the lack of clinical

manifestations of cortisol excess (34).

In patients whose personal or family history suggests

the possibility of a multiple endocrine neoplasia syn-

drome, additional screening and follow-up as appropriate

to the suspected syndrome should be undertaken.

1.1–1.1.1 Values and preferences

The recommendations for screening for hypersecretion

needed to balance the potential benefits of early detection

with the relatively low likelihood of finding certain ab-

normalities in a given patient and the costs and burden of

potentially unnecessary testing.

Screening for certain hormone hypersecretion syn-

dromes was considered important, even if the patient was

asymptomatic or if the abnormality was unlikely in the

patient population. Screening for hyperprolactinemia was

considered essential because of the potential for successful

treatment with an oral dopamine agonist. Screening for

GH excess with a serum IGF-I level was recommended

because early detection of a GH-secreting tumor, which

would likely be asymptomatic, could reduce long-term

morbidity and increase the likelihood of surgical cure.

Some consider screening also for glucocorticoid excess in

all patients, but others may limit screening to patients for

whom there is a clinical suspicion, due to the high false-

positive rate and low rate of true-positive testing in the

former group of patients.

1.1–1.1.1 Remarks

The pros and cons of detailed vs. limited screening for

hypersecretion syndromes (other than for prolactinoma)

were debated, and the Task Force was split on this point.

The quality of evidence for or against one particular test-

ing strategy was weak.

Recommendation

1.1.2 We recommend that patients with a pituitary in-

cidentaloma with or without symptoms also undergo

clinical and laboratory evaluations for hypopituitarism

(1ⱍQQQE).

1.1.2 Evidence

Evidence to support screening for hypopituitarism in

patients with an incidentaloma also comes from small ob-

servational studies. In combined data in micro- and mac-

roincidentalomas, hypopituitarism was present in seven of

66 (5) and 19 of 46 patients (7). Deficits of gonadotropins

(not associated with hyperprolactinemia) were detected in

up to 30% of patients (4, 7, 8), of the ACTH/cortisol axis

in up to 18% (7, 8), thyroid axis in up to 28% (7, 8), and

GH axis in up to 8% (4).

Different approaches can be taken to the initial evalu-

ation of the patient for hypopituitarism. Some Task Force

members recommend a minimal screening with the mea-

surement of free T

, morning cortisol, and testosterone

levels, whereas others recommend that the initial evalua-

tion should also include the measurement of TSH, LH, and

FSH and IGF-I. A broad initial approach to this testing is

favored by some to avoid the repeated blood sampling that

would be needed to confirm a central origin of target organ

deficiencies should they be detected. Low gonadotropin

levels in postmenopausal women provide evidence of hy-

popituitarism and in men exclude primary hypogonadism

when testosterone levels are low. Similarly, normal or low

TSH levels help distinguish a pituitary etiology of hypo-

thyroidism when the free T

is low. Gonadal function can

be assessed in premenopausal women by history and ex-

amination. If baseline testing suggests hypopituitarism,

further stimulation tests of the pituitary-adrenal or GH-

IGF-I axis should be performed.

1.1.2 Values and preferences

The size of the incidentaloma may also be relevant to

the risk of hypopituitarism, so the Task Force debated

whether the size should factor into the decision to screen

or not to screen for hypopituitarism. The Task Force more

strongly favored routine testing for hypopituitarism in

macroincidentalomas and larger microincidentalomas,

for example 6–9 mm, and not necessarily in smaller mi-

croincidentalomas because asymptomatic pituitary hor-

mone deficits can be detected and larger lesions seem more

likely to be associated with hypopituitarism. Although

there are no specific data on the prevalence of hypopitu-

itarism in larger vs. smaller microincidentalomas, in the

Task Force’s experience some larger microincidentalomas

may behave more like macroincidentalomas, which leads

some endocrinologists to routinely evaluate larger micro-

incidentalomas for hypopituitarism. Routine screening

for hypopituitarism among smaller microincidentalomas

may not be necessary because the rate of hypopituitarism

among them appears to be very low, although the number

of patients reported is very small (4, 8, 9). However, recent

data do show that hypopituitarism can occur in microad-

enomas (35). The Task Force recognized that there is a

continuum of size of pituitary incidentalomas, so a 1-cm

size cutoff may be arbitrary in evaluating the risk of hy-

popituitarism and other anatomic characteristics of the

incidentaloma need to be considered. The evidence was

downgraded because only observational data from rela-

898 Freda et al. Guidelines on Pituitary Incidentaloma J Clin Endocrinol Metab, April 2011, 96(4):894–904

tively small studies are available, and some decisions had

to be made based on the clinical experiences of the Task

Force members rather than rigorous studies.

1.1.2 Remarks

Our recommendations include routine screening for

GH deficiency (GHD) with an IGF-I level in all patients,

but the Task Force recognized that this alone is insufficient

evidence for or against GHD in adults. In patients with a

clinical suspicion of GHD, in particular if the IGF-I is low,

further testing should be undertaken as recommended in

the “Evaluation and Treatment of Adult Growth Hor-

mone Deficiency: an Endocrine Society Clinical Practice

Guideline” (36). The authors of this guideline also recog-

nized that the approach taken to the testing for and treat-

ment of GHD varies among endocrinologists and that

some would only consider performing the testing if the

clinical setting suggested the potential for a benefit of GH

therapy.

Recommendation

1.1.3 We recommend that all patients presenting with

a pituitary incidentaloma abutting or compressing the op-

tic nerves or chiasm on MRI undergo a

formal VF examination (1ⱍQQQQ).

1.1.3 Evidence

Baseline VF testing is recom-

mended for all patients with an inci-

dentaloma abutting the optic nerves

or chiasm, even without visual symp-

toms (Fig. 1). In one prospective study

of 11 macroincidentalomas, one pa-

tient had VF abnormalities, and two

had compression of the optic chiasm

(8). In other studies, 15% (32) and

5% (4) of patients had unrecognized

VF abnormalities at presentation.

Recommendation

1.1.4 We recommend that all pa-

tients have a MRI scan, if possible, to

evaluate the pituitary incidentaloma (if

the incidentaloma was initially only di-

agnosed by CT scan) to better delineate

the nature and extent of the incidenta-

loma (1ⱍQQQQ).

1.1.4 Remarks

For the MRI, a specific pituitary pro-

tocol should be done that includes fine

cuts thorough the sella with and with-

out the administration of the contrast

agent gadolinium. Guidelines for the evaluation of renal

function before administration of gadolinium should be

followed.

2.0 Follow-up testing of the pituitary

incidentaloma

Recommendations

2.1 Patients with incidentalomas who do not meet cri-

teria for surgical removal of the tumor should receive non-

surgical follow-up (2ⱍQQEE), with clinical assessments

and the following tests:

2.1.1 MRI scan of the pituitary 6 months after the ini-

tial scan if the incidentaloma is a macroincidentaloma and

1 yr after the initial scan if it is a microincidentaloma

(1ⱍQQEE). In patients whose incidentaloma does not

change in size, we suggest repeating the MRI every year for

macroincidentalomas and every 1–2 yr in microinciden-

talomas for the following 3 yr and gradually less fre-

quently thereafter (2ⱍQQEE).

2.1.2 VF testing in patients with a pituitary incidenta-

loma that enlarges to abut or compress the optic nerves or

chiasm on a follow-up imaging study (1ⱍQQQQ). We sug-

FIG. 1. Flow diagram for the evaluation and treatment of pituitary incidentalomas. a, Baseline

evaluation in all patients should include a history and physical exam evaluating for signs and

symptoms of hyperfunction and hypopituitarism and a laboratory evaluation for hypersecretion. b,

This group may also include large microlesions (see Section 2.1 Evidence). c, The recommendation

for surgery includes the presence of abnormalities of VF or vision and signs of tumor compression

(Section 3.1); surgery is also suggested for other findings (see Section 3.2). d, VF testing is

recommended for patients with lesions abutting or compressing the optic nerves or chiasm at the

initial evaluation and during follow-up. e, Evaluation for hypopituitarism is recommended for the

baseline evaluation and during follow-up evaluations. This is most strongly recommended for

macrolesions and larger microlesions (see Section 1.3). f, Repeat MRI in 1 yr, yearly for 3 yr, and

then less frequently thereafter if no change in lesion size. g, Repeat the MRI in 6 months, yearly

for 3 yr, and then less frequently if no change in lesion size. [Modified from Molitch ME: J Clin

Endocrinol Metab 80:3–6, 1995 (49).]

J Clin Endocrinol Metab, April 2011, 96(4):894–904 jcem.endojournals.org 899

gest 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

(2ⱍQEEE).

2.1.3 Clinical and biochemical evaluations for hypop-

ituitarism 6 months after the initial testing and yearly

thereafter in patients with a pituitary macroincidenta-

loma, although typically hypopituitarism develops with

the finding of an increase in size of the incidentaloma

(1ⱍQQEE). We suggest that clinicians do not need to test

for hypopituitarism in patients with pituitary microinci-

dentalomas whose clinical picture, history, and MRI do

not change over time (2ⱍQQEE).

2.1 Evidence

The options for treatment of patients with asymptomatic,

clinically nonfunctioning pituitary incidentalomas are con-

servative follow-up without surgery (Fig. 1) or immediate

surgery despite the lack of indications for this. Conservative

follow-up was recommended with the recognition that the

proper algorithm for this and its appropriateness and safety

have not been tested prospectively. Few data are available for

or against a nonsurgical approach to management of asymp-

tomatic pituitary incidentalomas. Therefore, evidence in

support of these guidelines also relied on the clinical experi-

ences of the Task Force members.

The proper algorithm for endocrine testing during this

follow-up has not been tested as prospectively conducted

endocrine testing of patients with pituitary incidentalo-

mas who were followed without surgery has only been

reported in 49 patients (8, 9). Follow-up endocrine testing

is recommended for patients with macroincidentalomas

because they are at risk of developing hypopituitarism. Of

the macroincidentalomas followed prospectively, wors-

ening hypopituitarism developed in one of seven (8) and

three of 28 (25) patients, all of whom had enlargement of

their tumors. Hypopituitarism also developed in four of

37 (5) and one of 248 (6) patients who developed apoplexy

on follow-up. Follow-up endocrine testing was recom-

mended despite the paucity of data because of the potential

high risk to the patient of untreated hypopituitarism. In a

meta-analysis of incidentaloma studies, new endocrine

dysfunction developed overall in 2.4% of patients per year

(3). It is unclear how often new hypopituitarism develops

in the absence of tumor growth. Rapid growth may in-

crease the risk of new hypopituitarism. Routine follow-up

endocrine testing is not required for microincidentalomas

whose clinical picture does not change because the risk of

developing new hypopituitarism is extremely low. In pre-

vious studies, none of the pituitary microincidentalomas

followed prospectively was reported to be associated with

changes in pituitary function (4–9).

The proposed algorithms for the MRI follow-up of pi-

tuitary incidentalomas took into account those adopted in

prior studies. However, those algorithms varied consid-

erably from study to study (4–9), and none was validated.

As a result, the imaging follow-up proposed in this guide-

line incorporated the experiences of the Task Force’s

members. Follow-up MRI scans were recommended for

macroincidentalomas because it has been demonstrated

that although generally these lesions grow slowly, some do

enlarge and become symptomatic. In data combined from

a number of studies, macroincidentalomas enlarged in 85

of 353 (24%) patients (4–9, 23–26). VF abnormalities

developed in 28 (8%) patients over time, which demon-

strated that the enlargement adversely affected the pa-

tient’s health. Pituitary apoplexy developed in seven of

353 (2%) patients, of whom most developed permanent

hypopituitarism and one had permanent vision impair-

ment (5). In a meta-analysis of these studies, 8.2% of in-

cidentalomas enlarged per year with a follow-up of 472

person-years (3). Less frequent surveillance of microinci-

dentalomas was recommended because their rate of en-

largement was low, being reported in 17 of 160 patients

(10.6%) followed from 2.3 to 7 yr (5–9, 23–25). In the

meta-analysis, 1.7% of microincidentalomas enlarged per

year (3). Importantly, none of the patients with these mi-

croincidentalomas developed new VF abnormalities that

would have necessitated surgery.

Overall, the Task Force considered that repeat scanning

within the first year was warranted for all patients because,

although most incidentalomas grow slowly, some do en-

large, and the true proliferative nature of the incidentaloma

is unknown (Fig. 1). If no growth is detected, then the interval

between MRI scans can be increased. Evidence does not sup-

port one particular algorithm for the frequency of follow-up

imaging, but we recommend repeating the MRI every year in

macroincidentalomas, every 1–2 yr in microincidentalomas

for the next 3 yr, and then every other year for the next 6 yr

and gradually less frequently indefinitely so long as the lesion

continues not to threaten the patient’s health. Some Task

Force members would continue imaging every 5 yr. Uncer-

tainty as to the optimal interval and duration of long-term

follow-up imaging can be shared with the patient, and the

scheme followed can be individualized to balance the phy-

sician’s assessment of the risk that the lesion poses to the

patient’s health with the burden to the patient of surveillance

testing.

2.1 Values and preferences

The decision to proceed with conservative nonsurgical

management of pituitary incidentalomas not meeting cri-

teria for surgery (see Section 3.0) puts a relatively high

value on avoiding surgical intervention and its associated

900 Freda et al. Guidelines on Pituitary Incidentaloma J Clin Endocrinol Metab, April 2011, 96(4):894–904

morbidity and cost, and a relatively low value in avoiding

apoplexy. The evidence that most incidentalomas do not

progress over time to cause visual or other disturbances

supports this value judgment. On the other hand, apo-

plexy developed in seven of 248 patients with incidenta-

lomas (4–6, 8, 9, 26). Large-scale prospective studies of

conservative nonsurgical management of pituitary inci-

dentalomas are needed to further inform this judgment.

2.1 Remarks

The Task Force recognized that a continuum of size of

incidentalomas exists, and some large microincidentalo-

mas (6–9 mm) may behave more like macroincidentalo-

mas. Therefore, some Task Force members would also

perform follow-up MRIs and hypopituitarism evaluations

in larger microincidentalomas as they would for macro-

incidentalomas. Some also considered that follow-up eval-

uations for hypopituitarism were needed only for patients

with enlarging incidentalomas because new hypopituitar-

ism would be very unlikely to develop without tumor

growth. However, no data are available to support one

particular size threshold for the increase in size that should

trigger this evaluation. The Task Force was split on these

points.

Recommendation

2.2 Patients who develop any signs or symptoms po-

tentially related to the incidentaloma or who show an in-

crease in size of the incidentaloma on MRI should undergo

more frequent or detailed evaluations as indicated clini-

cally (1ⱍQQEE).

3.0 Indications for surgical therapy of the pituitary

incidentaloma

Recommendation

3.1 We recommend that patients with a pituitary inci-

dentaloma be referred for surgery if they have the follow-

ing (1ⱍQQQQ):

•A VF deficit due to the lesion.

•Other visual abnormalities, such as ophthalmoplegia

or neurological compromise due to compression by

the lesion.

•Lesion abutting or compressing the optic nerves 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 (31, 33).

3.1 Evidence

The decision to recommend surgery as initial therapy for

a patient with a pituitary incidentaloma needs to be individ-

ualized (Fig. 1). Few data are available that specifically ex-

amine the outcome of surgery for incidentalomas. Some of

the evidence considered in developing the recommended cri-

teria for surgery was from transsphenoidal surgical series of

symptomatic and often large pituitary lesions. From these

data and based on the clinical experiences of the Task Force

members, it is clear that substantial evidence supports the

need for surgery for pituitary incidentalomas causing visual

or neurological compromise. The presence of visual or neu-

rological abnormalities due to compression of the optic

nerves or chiasm by the incidentaloma is the strongest indi-

cation for surgery. Although the risks of not performing sur-

gery on tumors that abut the chiasm or for those within cer-

tain proximity of the chiasm but where no VF abnormalities

are present have not been quantified, in the Task Force’s

experience significant risk of future vision disturbance in

these patients exists to warrant surgery. The age of the patient

is also an important consideration. Surgery may be favored

in younger vs. older patients given the higher lifetime prob-

ability of tumor enlargement in the former and the greater

risks of surgical intervention in the latter group of patients.

Some may elect to follow elderly patients with significant

risks to surgery conservatively and closely for any deterio-

ration in vision. The decision to recommend surgery should

also consider whether future fertility is of concern to the pa-

tient. Difficult cases could also be discussed at a pituitary

multidisciplinary team meeting when this is available.

Surgery is indicated in patients with apoplexy and

visual disturbance. In a retrospective review of 30 sub-

jects with pituitary apoplexy, the 20 who were followed

conservatively had a similar long-term risk of hypopi-

tuitarism as those treated surgically (37). Therefore,

patients with apoplexy and without visual compromise

may be followed conservatively with serial imaging and

hormonal assessments.

3.1 Values and preferences

Our recommendations for surgery for incidentalomas put

a high value on alleviating or preventing visual or neurolog-

ical compromise. Although the benefits of surgery in pre-

venting future visual abnormalities are not known, a rela-

tively higher value was put on the prevention of VF

abnormalities than on avoiding the morbidity (e.g. diabetes

insipidus, hypopituitarism) and the cost of surgery. New hy-

popituitarism as a result of transsphenoidal surgery is rare in

the Task Force’s experience, but the risk should be consid-

ered in the clinical context of the particular patient.

3.1 Remarks

The recommendations for surgical therapy of a pitu-

itary incidentaloma were based on the Task Force’s ex-

pectations for outcome and improvements in vision and

J Clin Endocrinol Metab, April 2011, 96(4):894–904 jcem.endojournals.org 901

endocrine function. These expectations were based on

known literature and Task Force members’ clinical expe-

rience with surgery performed by a surgeon experienced in

transsphenoidal pituitary surgery. The success of surgery

for hormone-secreting tumors is highly dependent on the

expertise, skill, and case volume of a pituitary surgeon

supported by an experienced team (38, 39). This is likely

to also be true for pituitary surgery of other types of le-

sions. The availability of such a pituitary surgeon needs to

be considered when following these guidelines.

Recommendation

3.2 We suggest that surgery be considered for patients

with a pituitary incidentaloma if they have the following

(2ⱍQQEE):

•Clinically significant growth of the pituitary

incidentaloma.

•Loss of endocrinological function.

•A lesion close to the optic chiasm and a plan to be-

come pregnant.

•Unremitting headache.

3.2 Evidence

The evidence for or against a recommendation for sur-

gery because of growth of a pituitary incidentaloma is

limited. Surgery was suggested for incidentalomas that

demonstrate clinically significant growth on follow-up

imaging studies, which is growth that could pose a health

risk to the patient such as to their vision. Such growing

incidentalomas typically continue to grow, and surgery is

most effective for smaller lesions. A specific size cutoff for

the incidentaloma was not considered a requirement for

surgery because some large incidentalomas are predomi-

nantly intra- and infrasellar. Although there are no estab-

lished changes in size or growth rate that would automat-

ically trigger the need for surgery, the pattern of growth of

the incidentaloma was considered more important. For

example, a 1-mm enlargement within the sella of a 5-mm

intrasellar microadenoma would not be clinically signifi-

cant, but a 1-mm enlargement toward the chiasm in a

lesion only 3 mm from the chiasm would be significant.

Therefore, incidentalomas exhibiting significant growth

(which includes growth that is rapid, occurring over a 1-

to 2-yr period, and/or that is toward the optic chiasm and

if continued could threaten vision in the near future)

should be considered for surgery before the incidentaloma

progresses to abut the chiasm or produce visual deficits. A

consideration of the clinical characteristics of the patient

including their age and other risks for surgery needs to be

incorporated into the decision to proceed to surgery.

The evidence for or against a recommendation for sur-

gery because of the presence of hypopituitarism is also

limited. Although some surgical series of symptomatic in-

cidentalomas show that hypopituitarism can improve

with surgery (40, 41), these data may not be applicable to

the incidentaloma, and as a result hypopituitarism was

considered only a relative indication for surgery. Adequate

replacement therapy should be instituted whether or not

surgery is recommended. Some patients planning preg-

nancy may benefit from surgery if their tumor is close to

the optic chiasm because there is a small risk that lac-

totroph hyperplasia in the normal gland may lead to tumor

compression of the optic nerve or chiasm, and closer fol-

low-up in such patients should be undertaken. Headache

may or may not improve with transsphenoidal removal of

the tumor, so it can only be suggested as an indication for

surgery, and the quality of evidence is low.

Medical therapy of the pituitary incidentaloma

In patients with incidentalomas and hyperprolactine-

mia that may be due to tumoral compression of the hy-

pothalamic-pituitary stalk, symptomatic hyperprolactine-

mia may be treated with a dopamine agonist. However,

incidentalomas other than a prolactinoma will rarely

shrink, and dopamine agonists cannot be relied upon for

this purpose. Therefore, continued monitoring of lesion

size is necessary, regardless of changes in prolactin levels.

Medical therapy of pituitary incidentalomas has not

been systematically studied. Some parallels to the effects of

medical therapy on pathologically confirmed nonfunc-

tioning pituitary tumors are possible, but this connection

needs to be made cautiously. The reported efficacy of do-

pamine agonist therapy of nonfunctioning pituitary ade-

nomas varies widely. With cabergoline or bromocriptine

treatment for patients with residual tumor after surgery,

some degree of tumor shrinkage was detected in 8–45%

(42–44), and the amount of shrinkage varied from 10–

62% (43, 44) or 3–14 mm (42). Somatostatin analogs have

also been tried. With no more than 1 yr of octreotide ther-

apy, shrinkage was reported in approximately 5–25%,

increase in 12%, and stabilization in 83% of tumors (45–

48). Insufficient data are available to suggest the routine

use of medical therapy of pituitary incidentalomas.

Acknowledgments

The members of the Task Force thank The Endocrine Society’s

Clinical Guidelines Subcommittee, Clinical Affairs Core Com-

mittee, and Council for their careful, critical review of earlier

versions of this manuscript and their helpful comments and sug-

gestions. We also thank the leadership of the European Society

of Endocrinology for their review and comments. In addition, we

thank the many members of The Endocrine Society who re-

viewed the draft version of this manuscript when it was posted

902 Freda et al. Guidelines on Pituitary Incidentaloma J Clin Endocrinol Metab, April 2011, 96(4):894–904

on the Society’s web site and who sent a great number of addi-

tional comments and suggestions, most of which were incorpo-

rated into the final version of the manuscript. Finally, we thank

the staff at the Society office for their helpful support during the

development of this guideline.

Address all correspondence and requests for reprints to: The

Endocrine Society, 8401 Connecticut Avenue, Suite 900, Chevy

Chase, MD 20815. E-mail: govt-prof@endo-society.org, Tele-

phone: 301-941-0200. Address all commercial reprint requests

for orders 101 and more to: Walchli Tauber Group Inc., E-mail:

Karen.burkhardt@wt-group.com. Address all reprint requests

for orders for 100 or fewer to Society Services, Telephone: 301-

941-0210, E-mail: societyservices@endo-society.org, or Fax:

301-941-0257.

Cosponsoring Associations: European Society of Endocrinology.

Financial Disclosures of the Task Force: Pamela U. Freda,

M.D.*—Financial or Business/Organizational Interests: No-

vartis, Ipsen, and Pfizer; Significant Financial Interest or Lead-

ership Position: none declared. Albert M. Beckers, M.D., D.Sc.,

Ph.D.—Financial or Business/Organizational Interests: No-

vartis, Ipsen, and Pfizer; Significant Financial Interest or Lead-

ership Position: none declared. Laurence Katznelson, M.D.—

Financial or Business/Organizational Interests: Novartis, Ipsen,

and Novo Nordisk; Significant Financial Interest or Leadership

Position: none declared. Mark E. Molitch, M.D.—Financial or

Business/Organizational Interests: Tercica/Ipsen, Novartis; Sig-

nificant Financial Interest or Leadership Position: none declared.

Victor M. Montori, M.D.*—Financial or Business/Organiza-

tional Interests: KER Unit (Mayo Clinic); Significant Financial

Interest or Leadership Position: none declared. Kalmon D. Post,

M.D. —Financial or Business/Organizational Interests: none de-

clared; Significant Financial Interest or Leadership Position:

none declared. Mary Lee Vance, M.D.—Financial or Business/

Organizational Interests: Novartis; Significant Financial Interest

or Leadership Position: none declared.

*Evidence-based reviews for this guideline were prepared un-

der contract with The Endocrine Society.

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