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Guideline Summary
Guideline Title
American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas.
Bibliographic Source(s)
Zeiger MA, Thompson GB, Duh QY, Hamrahian AH, Angelos P, Elaraj D, Fishman E, Kharlip J, American Association of Clinical Endocrinologists, American Association of Endocrine Surgeons. The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas. Endocr Pract. 2009 Jul-Aug;15 Suppl 1:1-20. [137 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)

Adrenal incidentalomas, including:

  • Cortisol-producing adenomas
  • Subclinical Cushing syndrome
  • Pheochromocytomas
  • Aldosteronomas
  • Adrenocortical carcinomas
  • Metastatic disease

Note: Adrenal incidentaloma is a term coined in reference to the phenomenon of detecting an otherwise unsuspected adrenal mass on radiologic imaging.

Guideline Category
Diagnosis
Evaluation
Management
Screening
Treatment
Clinical Specialty
Endocrinology
Oncology
Radiology
Intended Users
Allied Health Personnel
Health Care Providers
Physicians
Guideline Objective(s)

To assist health care providers in medical decision making related to the diagnosis and management of adrenal incidentalomas

Target Population

Patients with adrenal incidentalomas

Interventions and Practices Considered

Diagnosis and Evaluation

  1. Clinical evaluation, history, and physical examination
  2. Biochemical evaluation
    • Dexamethasone suppression test, late-night salivary cortisol, and 24-hour urine-free cortisol (UFC) test for cortisol-producing adenomas
    • Dexamethasone suppression test or 24-hour UFC test for subclinical Cushing syndrome
    • 24-hour urine total metanephrines or plasma free metanephrines and normetanephrines for pheochromocytoma
    • Ratio of plasma aldosterone concentration (PAC) to plasma renin activity (PRA) for aldosteronoma
    • Hormone testing for adrenocortical carcinoma
  3. Imaging studies
    • Computed tomography (CT) scanning with use of a contrast agent for pheochromocytoma
    • Enhanced CT and adrenal venous sampling (AVS) for aldosteronoma
    • Noncontrast CT for adrenocortical carcinoma
    • Contrast-enhanced CT of the chest, abdomen, and pelvis; site specific magnetic resonance imaging (MRI) or fluorodeoxyglucose (18F) positron emission tomography (FDG-PET)/CT (or both); and bone scanning for metastatic disease
    • CT-guided fine needle aspiration (FNA) for metastatic disease
  4. Genetic testing in pheochromocytoma
  5. Diagnosis of malignancy
  6. Referral to an endocrinologist or endocrine surgeon for assessment

Management and Treatment

  1. Surgical resection
  2. Medical treatment and management
    • Glucocorticoid replacement after surgical resection of adenomas
    • Calcium channel blockers for management of pheochromocytoma
    • Spironolactone or eplerenone for aldosteronoma
  3. Follow-up
Major Outcomes Considered
  • Differential diagnosis of adrenal incidentalomas
  • Sensitivity and specificity of diagnostic tests
  • Disease recurrence

Methodology

Methods Used to Collect/Select the Evidence
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

PubMed was used for all searches; the years were not defined. Search words included "adrenal incidentaloma," "hyperaldosteronoma," "hyperaldosteronism," "Cushing's syndrome," and "pheochromocytoma."

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Levels of Scientific Substantiation in Evidence-Based Medicine*

Level Description Comments

1

Prospective, randomized, controlled trials—large

Data are derived from a substantial number of trials, with adequate statistical power involving a substantial number of outcome data subjects

Large meta-analyses using raw or pooled data or incorporating quality ratings

Well-controlled trial at one or more centers

Consistent pattern of findings in the population for which the recommendation is made (generalizable data)

Compelling nonexperimental, clinically obvious evidence (for example, use of insulin in diabetic ketoacidosis); "all-or-none" indication

2

Prospective controlled trials with or without randomization—limited body of outcome data

Limited number of trials, small population sites in trials

Well-conducted single-arm prospective cohort study

Limited but well-conducted meta-analyses

Inconsistent findings or results not representative for the target population

Well-conducted case-controlled study

3

Other experimental outcome data and nonexperimental data

Nonrandomized, controlled trials

Uncontrolled or poorly controlled trials

Any randomized clinical trial with 1 or more major or 3 or more minor methodologic flaws

Retrospective or observational data

Case reports or case series

Conflicting data with weight of evidence unable to support a final recommendation

4

Expert opinion

Inadequate data for inclusion in level 1, 2, or 3; necessitates an expert panel's synthesis of the literature and a consensus

Experience-based

Theory-driven

*Levels 1, 2, and 3 represent a given level of scientific substantiation or proof. Level 4 or Grade D represents unproven claims. It is the "best evidence" based on the individual ratings of clinical reports that contributes to a final grade recommendation (see the "Rating Scheme for the Strength of the Recommendations" field).

Methods Used to Analyze the Evidence
Systematic Review
Description of the Methods Used to Analyze the Evidence

Criteria used included only the authors' expert opinions about the relevant papers.

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

In 2004, the American Association of Clinical Endocrinologists (AACE) Protocol for Standardized Production of Clinical Practice Guidelines was published in Endocrine Practice. Those recommendations were used for the preparation of this document. The American Association of Endocrine Surgeons (AAES) and AACE cochairpersons and primary writers are experts in the clinical management of adrenal diseases. After the completion of the first draft created by the primary writers, the chairpersons reviewed the technical assignment of evidence levels (inserted in the reference list and in the text) and recommendation grades (in the Executive Summary).

Rating Scheme for the Strength of the Recommendations

Grade-Recommendation Protocol Adopted by the American Association of Clinical Endocrinologists*

Grade Description Recommendation

A

≥1 conclusive level 1 publications demonstrating benefit >> risk

Action recommended for indications reflected by the published reports

Action based on strong evidence

Action can be used with other conventional therapy or as first-line therapy

B

No conclusive level 1 publication

≥1 conclusive level 2 publications demonstrating benefit >> risk

Action recommended for indications reflected by the published reports

If the patient refuses or fails to respond to conventional therapy; must monitor for adverse effects, if any

Action based on intermediate evidence

Can be recommended as second-line therapy

C

No conclusive level 1 or 2 publication

≥1 conclusive level 3 publications demonstrating benefit >> risk

or

No risk at all and no benefit at all

Action recommended for indications reflected by the published reports

If the patient refuses or fails to respond to conventional therapy, provided there are no significant adverse effects; "no objection" to recommending their use

or

"No objection" to continuing their use

Action based on weak evidence

D

No conclusive level 1, 2, or 3 publication demonstrating benefit >> risk

Conclusive level 1, 2, or 3 publications demonstrating risk >> benefit

Not recommended

Patient is advised to discontinue use

Action not based on any evidence

*The final recommendation grades were determined by the primary writers by consensus on the basis of (1) "best evidence" ratings (see the "Rating Scheme for the Strength of the Evidence" field) and (2) subjective factors.

Cost Analysis

A cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation
Internal Peer Review
Description of Method of Guideline Validation

The document was subsequently reviewed by the American Association of Endocrine Surgeons (AAES) and American Association of Clinical Endocrinologists (AACE) publication and executive committees and then finally completed by the chairpersons.

Recommendations

Major Recommendations

The levels of evidence (1 to 4) and the recommendation grades (A to D) are defined at the end of the "Major Recommendations" field.

Executive Summary of Recommendations

This current set of clinical practice guidelines summarizes the relevant literature as it pertains to the differential diagnosis, laboratory and radiologic evaluation, and clinical management and includes recommendations (each labeled "R" in the subsequent section) based on the "best evidence" rating level (BEL) of the published sources.

R1. Patients with an adrenal incidentaloma should undergo evaluation clinically, biochemically, and radiographically for signs and symptoms of hypercortisolism, aldosteronism (if hypertensive), the presence of a pheochromocytoma, or a malignant tumor (Grade C; BEL 3).

R2. Patients with adrenal incidentalomas who do not fulfill the criteria for surgical resection need to have radiographic reevaluation at 3 to 6 months and then annually for 1 to 2 years. For all adrenal tumors, hormonal evaluation should be performed at the time of diagnosis and then annually for 5 years (Grade C; BEL 3).

R3. All patients found to have an incidental adrenal mass should be screened for cortisol excess. Although the best strategy for patients with incidentalomas has not been established, the simplest screening test for autonomous cortisol secretion from an incidentaloma is a 1-mg overnight dexamethasone suppression test. If clinical suspicion is high, such as in patients with hypertension, obesity, diabetes mellitus, or osteoporosis, 3 tests (salivary cortisol, dexamethasone suppression, and urine free cortisol [UFC]) can be used (Grade C; BEL 3).

R4. After adrenalectomy for a cortisol-producing adenoma, patients should be treated with exogenous glucocorticoids until the hypothalamic-pituitary-adrenal (HPA) axis has recovered. This process may take 6 to 18 months after unilateral adrenalectomy (Grade C; BEL 3).

R5. A diagnosis of subclinical Cushing syndrome (SCS) is made if the serum cortisol level is more than 5.0 mcg/dL after a 1-mg dexamethasone suppression test, in a patient with an adrenal adenoma and absence of typical physical stigmas of hypercortisolism. A low or suppressed level of adrenocorticotropic hormone (ACTH) or a low dehydroepiandrosterone sulfate concentration supports the diagnosis (Grade D; BEL 4). A second abnormal test result of HPA axis function, such as a 2-day low-dose dexamethasone suppression test, may also be needed to establish the diagnosis of SCS (Grade B; BEL 2).

R6. In patients with SCS, until further evidence is available regarding the long-term benefits of adrenalectomy, surgical resection should be reserved for those with worsening of hypertension, abnormal glucose tolerance, dyslipidemia, or osteoporosis (Grade D; BEL 4).

R7. Perioperative glucocorticoid therapy and postoperative assessment of HPA axis recovery are indicated in patients with SCS (Grade C; BEL 3).

R8. Patients thought to have a pheochromocytoma should undergo measurement of plasma fractionated metanephrines and normetanephrines or 24-hour total urinary metanephrines and fractionated catecholamines (or both plasma and urine studies) (Grade A; BEL 1).

R9. About one-quarter of patients with a pheochromocytoma will have associated familial syndromes caused by mutations in the RET gene (multiple endocrine neoplasia type 2), VHL gene (von Hippel-Lindau disease), or succinate dehydrogenase genes; genetic study and counseling should be performed, especially for young patients or patients with an extra-adrenal pheochromocytoma (Grade C; BEL 3).

R10. Surgical resection should be performed for all pheochromocytomas (Grade C; BEL 3).

R11. In all patients with a pheochromocytoma, an alpha-adrenergic blocking agent should be administered preoperatively, in an effort to prevent intraoperative hemodynamic instability (Grade C; BEL 3).

R12. In patients who have undergone resection of a pheochromocytoma, long-term follow-up is necessary because 10% to 15% may have recurrence (Grade B; BEL 2).

R13. Screening for aldosteronism should be performed in patients with an aldosterone-to-renin ratio (ARR) of >20 (Grade C; BEL 3).

R14. Primary aldosteronism is confirmed in the setting of an adrenal incidentaloma by demonstrating lack of aldosterone suppression (24-hour urine study) with salt loading (Grade C; BEL 3).

R15. Subtype evaluation should be achieved with high-resolution computed tomographic (CT) scanning in all patients and adrenal venous sampling (AVS) in the majority of patients older than 40 years (Grade C; BEL 3).

R16. In patients with primary aldosteronism and a unilateral source of aldosterone excess, laparoscopic total adrenalectomy is the treatment of choice because it yields excellent outcomes with low associated morbidity relative to open approaches (Grade C; BEL 3).

R17. Patients with bilateral idiopathic hyperaldosteronism (IHA) or those not amenable or agreeable to surgical intervention should be managed with selective and nonselective mineralocorticoid receptor blockers (Grade A; BEL 1).

R18. Any adrenal mass with concerning radiographic characteristics and most lesions ≥4 cm should be resected because of increased risk of adrenal cancer (Grade C; BEL 3).

R19. The presence of pheochromocytoma should be ruled out biochemically before an attempted resection of any adrenal mass (Grade C; BEL 3).

R20. All patients suspected of having an adrenocortical carcinoma (ACC) should undergo biochemical evaluation to identify any potential hormone excess that serves as a tumor marker and to determine whether the patient requires steroid replacement perioperatively in cases of hypercortisolism (Grade D; BEL 4).

R21. Open adrenalectomy should be performed if ACC is suspected (Grade C; BEL 3).

R22. A metastatic lesion should be suspected in a patient with a history of cancer and an adrenal mass that does not fulfill the criteria for an incidentaloma (Grade C; BEL 3).

R23. In very rare instances, pathologic confirmation with CT-guided needle biopsy may be required for staging and planning of oncologic treatments (Grade D; BEL 4).

R24. The presence of pheochromocytoma should be ruled out with biochemical testing before performance of a biopsy (Grade C; BEL 3).

R25. Patients with bilateral adrenal metastatic lesions should undergo evaluation for adrenal insufficiency (Grade D; BEL 4).

R26. Adrenal metastasectomy is rarely indicated but should be considered in the case of an isolated adrenal metastatic lesion (Grade C; BEL 3).

Definitions:

Levels of Scientific Substantiation in Evidence-Based Medicine*

Level Description Comments

1

Prospective, randomized, controlled trials—large

Data are derived from a substantial number of trials, with adequate statistical power involving a substantial number of outcome data subjects

Large meta-analyses using raw or pooled data or incorporating quality ratings

Well-controlled trial at one or more centers

Consistent pattern of findings in the population for which the recommendation is made (generalizable data)

Compelling nonexperimental, clinically obvious evidence (for example, use of insulin in diabetic ketoacidosis); "all-or-none" indication

2

Prospective controlled trials with or without randomization—limited body of outcome data

Limited number of trials, small population sites in trials

Well-conducted single-arm prospective cohort study

Limited but well-conducted meta-analyses

Inconsistent findings or results not representative for the target population

Well-conducted case-controlled study

3

Other experimental outcome data and nonexperimental data

Nonrandomized, controlled trials

Uncontrolled or poorly controlled trials

Any randomized clinical trial with 1 or more major or 3 or more minor methodologic flaws

Retrospective or observational data

Case reports or case series

Conflicting data with weight of evidence unable to support a final recommendation

4

Expert opinion

Inadequate data for inclusion in level 1, 2, or 3; necessitates an expert panel's synthesis of the literature and a consensus

Experience-based

Theory-driven

*Levels 1, 2, and 3 represent a given level of scientific substantiation or proof. Level 4 or Grade D represents unproven claims. It is the "best evidence" based on the individual ratings of clinical reports that contributes to a final grade recommendation (see the "Rating Scheme for the Strength of the Recommendations" field).

Grade-Recommendation Protocol Adopted by the American Association of Clinical Endocrinologists*

Grade Description Recommendation

A

≥1 conclusive level 1 publications demonstrating benefit >> risk

Action recommended for indications reflected by the published reports

Action based on strong evidence

Action can be used with other conventional therapy or as first-line therapy

B

No conclusive level 1 publication

≥1 conclusive level 2 publications demonstrating benefit >> risk

Action recommended for indications reflected by the published reports

If the patient refuses or fails to respond to conventional therapy; must monitor for adverse effects, if any

Action based on intermediate evidence

Can be recommended as second-line therapy

C

No conclusive level 1 or 2 publication

≥1 conclusive level 3 publications demonstrating benefit >> risk

or

No risk at all and no benefit at all

Action recommended for indications reflected by the published reports

If the patient refuses or fails to respond to conventional therapy, provided there are no significant adverse effects; "no objection" to recommending their use

or

"No objection" to continuing their use

Action based on weak evidence

D

No conclusive level 1, 2, or 3 publication demonstrating benefit >> risk

Conclusive level 1, 2, or 3 publications demonstrating risk >> benefit

Not recommended

Patient is advised to discontinue use

Action not based on any evidence

*The final recommendation grades were determined by the primary writers by consensus on the basis of (1) "best evidence" ratings (see the "Rating Scheme for the Strength of the Evidence" field) and (2) subjective factors.

Clinical Algorithm(s)

The original guideline document contains algorithms for:

  • The evaluation and management of an adrenal incidentaloma
  • Use of plasma renin activity (PRA) and plasma aldosteronism (PAC) and their ratio (PAC/PRA) for diagnosing aldosteronism in patients with resistant hypertension, hypokalemia, or both
  • Confirmation of primary aldosteronism

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations").

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate management of patients with adrenal incidentalomas

Potential Harms
  • The risks of fine needle aspiration (FNA) are well described and include adrenal hematoma or abscess, abdominal pain, hematuria, pancreatitis, pneumothorax, and tumor recurrence in the biopsy track. The patient should undergo biochemical evaluation for pheochromocytoma before biopsy, in light of the risk of fatal hypertensive crisis during FNA.
  • Although enhanced computed tomography (CT) imaging for aldosteronomas reduces the number of false-negative studies, it clearly increases the number of studies with false-positive results that could lead to either inappropriate withholding of surgical intervention or surgical removal of the wrong gland. This challenge becomes more important with advancing age as the incidence of adrenal incidentalomas increases.
  • Although the urinary measurements used for detection of pheochromocytoma have a higher false-negative rate, the plasma levels are associated with a higher false-positive rate. Use of tricyclic antidepressants, decongestants, amphetamines, reserpine, and phenoxybenzamine should be discontinued to eliminate the likelihood of a false-positive result.
  • Side effects of phenoxybenzamine, used to prepare patients for surgical treatment of pheochromocytoma, include orthostatic hypotension, tachycardia, nasal congestion, nausea, or abdominal pain.

Qualifying Statements

Qualifying Statements
  • The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas are systematically developed statements to assist health care providers in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied.
  • These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual circumstances.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools
Clinical Algorithm
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
Living with Illness
IOM Domain
Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
Zeiger MA, Thompson GB, Duh QY, Hamrahian AH, Angelos P, Elaraj D, Fishman E, Kharlip J, American Association of Clinical Endocrinologists, American Association of Endocrine Surgeons. The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas. Endocr Pract. 2009 Jul-Aug;15 Suppl 1:1-20. [137 references] PubMed External Web Site Policy
Adaptation

Not applicable: This guideline was not adapted from another source.

Date Released
2009 Jul-Aug
Guideline Developer(s)
American Association of Clinical Endocrinologists - Medical Specialty Society
American Association of Endocrine Surgeons - Medical Specialty Society
Source(s) of Funding

American Association of Clinical Endocrinologists (AACE)

American Association of Endocrine Surgeons (AAES)

Guideline Committee

Adrenal Incidentalomas Writing Committee

Composition of Group That Authored the Guideline

Writing Committee

Cochairpersons: Martha A. Zeiger, MD, FACS, FACE; Geoffrey B. Thompson, MD, FACS, FACE; Quan-Yang Duh, MD, FACS; Amir H. Hamrahian, MD, FACE

Primary Writers: Martha A. Zeiger, MD, FACS, FACE; Geoffrey B. Thompson, MD, FACS, FACE; Quan-Yang Duh, MD, FACS; Peter Angelos, MD, PhD, FACS, FACE; Dina Elaraj, MD; Elliot Fishman, MD; Amir H. Hamrahian, MD, FACE; Julia Kharlip, MD

Reviewers

American Association of Clinical Endocrinologists: Jeffrey R. Garber, MD, FACP, FACE; Jeffrey I. Mechanick, MD, FACP, FACE, FACN

American Association of Endocrine Surgeons: Michael J. Demeure, MD, MBA, FACS, FACE; William B. Inabnet, MD, FACS

Financial Disclosures/Conflicts of Interest

Cochairpersons/Primary Writers

Dr. Martha A. Zeiger reports that she does not have any relevant financial relationships with any commercial interests.

Dr. Geoffrey B. Thompson reports that he does not have any relevant financial relationships with any commercial interests.

Dr. Quan-Yang Duh reports that he has received advisory board honoria from Covidien.

Dr. Amir H. Hamrahian reports that he does not have any relevant financial relationships with any commercial interests.

Primary Writers

Dr. Peter Angelos reports that he has received faculty honoraria from Ethicon Endo-Surgery, Inc.

Dr. Dina Elaraj reports that she does not have any relevant financial relationships with any commercial interests.

Dr. Elliot Fishman reports that he has received research grant support from GE Healthcare and Siemens AG.

Dr. Julia Kharlip reports that she does not have any relevant financial relationships with any commercial interests.

American Association of Clinical Endocrinologists Reviewers

Dr. Jeffrey R. Garber reports that he does not have any relevant financial relationships with any commercial interests.

Dr. Jeffrey I. Mechanick reports that he does not have any relevant financial relationships with any commercial interests.

American Association of Endocrine Surgeons Reviewers

Dr. Michael J. Demeure reports that he does not have any relevant financial relationships with any commercial interests.

Dr. William B. Inabnet reports that he has received research grant support from Covidien.

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available in Portable Document Format (PDF) from the American Association of Clinical Endocrinologists (AACE) Web site External Web Site Policy.

Print copies: Available from the American Association of Clinical Endocrinologists (AACE), 1000 Riverside Avenue, Suite 205, Jacksonville, FL 32204.

Availability of Companion Documents

The following is available:

Print copies: Available from the American Association of Clinical Endocrinologists (AACE), 1000 Riverside Avenue, Suite 205, Jacksonville, FL 32204.

Patient Resources

None available

NGC Status

This summary was completed by ECRI Institute on March 7, 2011.

Copyright Statement

All rights reserved. No part of these materials may be reproduced or retransmitted in any manner without the prior written permission of American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE).

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