AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Adrenal masses (AMs) are often discovered incidentally and are then termed adrenal incidentalomas (AIs). They are often discovered after an imaging procedure is performed that is unrelated to the adrenal gland. Usually, the patient has no signs of hormonal excess or obvious underlying malignancy. Incidence has been increasing proportionally to the use of radiographic imaging.

Less commonly, AMs are discovered as part of the clinical workup for suspected adrenal disease (eg, Cushing syndrome). Much of the following discussion is on the clinical conundrum of the incidentally discovered AM. The term adrenal adenoma (AA) is used in the following discussion when nonadrenal sources occupying the adrenal area can be excluded. The term AM is used when a nonadrenal space-occupying structure cannot be excluded.

Pathophysiology

The 2 main concerns with regard to an AI are (1) whether it is hormonally active and (2) whether it is malignant. The treatment for a hormonally active adrenal tumor is surgery. The treatment for a malignancy depends on the cell type, spread, and location of the primary tumor.

Frequency

United States

The autopsy prevalence for AMs is 2-9% (see Table 1). Approximately 1-10% of CT scans and MRIs detect AIs that are 5 mm or larger.

Table 1. Prevalence of AMs

Author	Method	Sample Size	Prevalence, %
Russl (1941)	Autopsy (>1 cm)	131/9000	1.5
Kokko (1967)	Autopsy (>5 mm)	21/1495	1.5
Hedeland (1967)	Autopsy (>2 mm)	64/739	8.7
Glazer (1982)	CT scan	16/2200	0.7
Abecassis (1985)	CT scan	19/1459	1.3
Belldegrun (1986)	CT scan	88/12000	0.7
Herrera (1991)	CT scan	259/61054	0.4

Mortality/Morbidity

• Prognosis varies depending on the underlying disease.
• Approximately 80% of AAs are nonfunctioning and benign.
• Twenty percent of AAs are either functioning or malignant and require further evaluation and treatment to avoid medical complications.

Race

No racial predilection has been reported.

Sex

AIs have a female sex predilection, probably reflecting the sex distribution of imaging procedures. Autopsy studies, however, show no sex preference for AAs.

Age

Prevalence increases with age; the rate is less than 1% for patients younger than 30 years and is 7% for patients 70 years or older.

CLINICAL

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History

• Pheochromocytomalike symptoms include episodic attacks, palpitations, sweats, headaches, and abdominal pain.
• Primary hyperaldosteronism includes hypertension and unprovoked hypokalemia.
• Adrenal carcinoma patients report weight loss, virilization, and feminization.
• Cushing syndrome includes weight gain, weakness, depression, and bruising.
• Evidence of hormonal excess includes the following:
• • Cushing syndrome for cortisol-secreting adenomas
  • Hypertension and hypokalemia for hyperaldosteronism
  • Labile hypertension and spells for pheochromocytoma
  • Virilization in women for androgen-secreting tumors
  • Feminization in men for estrogen-secreting tumors
• If clinical evidence manifests, perform diagnostic hormonal testing (see Table 2).

  Table 2. Evaluation of AM Syndromes

  Diagnosis	Features	Biochemical Tests
  Pheochromocytoma	High blood pressure, catechol symptoms	Urine- and plasma-free metanephrines
  Primary aldosteronism	High blood pressure, low K+, low PRA*	Plasma aldosterone-to-renin ratio
  Adrenocortical carcinoma	Virilization or feminization	Urine 17-ketosteroids
  Cushing or "silent" Cushing syndrome	Cushing symptoms or normal examination results	Overnight 1-mg dexamethasone test

  *Plasma renin activity
• Evidence of systemic disease, such as carcinoma, amyloidosis, or granulomatous disease, may be present.
• Often, no clinical clues can be found and other information is needed for diagnosis.

Physical

• Vital signs may include findings of high blood pressure, postural hypotension, and tachycardia.
• A fundi feature is hypertensive retinopathy.
• Skin findings include hirsutism and striae.
• General signs are central obesity and gynecomastia.
• Mass size is an important predictive characteristic.
• • Larger tumors are more likely to be malignant.
  • The cutoff criterion for suspicion of malignancy ranges from 3-6 cm in diameter.
  • The best hope for a surgical cure is a lower cutoff, but this means a greater number of benign tumors will be removed unnecessarily.
  • A 4-cm cutoff is estimated to result in an acceptable ratio of 1 cancerous to 8 benign tumors (see Image 1).

Causes

• The biochemical mechanisms depend on the underlying cell type.
• The cellular mechanisms for primary adrenocortical tumorigenesis are just beginning to be understood.
• Some studies report an association with chromosomal and genetic abnormalities (genes coding for p53 and p57).
• Tumor markers are also present in other syndromes.
• • The multiple endocrine neoplasia (MEN1) gene is linked to multiple endocrine neoplasia type 1.
  • The aldosynthase/11-beta hydroxylase hybrid gene is associated with glucocorticoid-remediable hyperaldosteronism.

DIFFERENTIALS

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Other Problems to be Considered

Adjacent structures masquerading as AMs (eg, kidneys, spleen, pancreas, lymph nodes)
Adrenal cortical hyperplasia
Adrenal cortical neoplasms
Infiltrative diseases
Hemorrhage
Lung cancer, adenocarcinoma
Medullary neoplasms
Metastatic disease (see Image 2)
Teratoma, atypical

WORKUP

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Lab Studies

• Because AAs may be hormonally silent, biochemical screening is warranted.
• Most frequently, cortisol produces subclinical Cushing syndrome.
• • This occurs when the AA autonomously secretes cortisol at levels high enough to suppress corticotropin but too low to produce Cushing stigmata.
  • Patients do not have increased rates of hypertension or diabetes mellitus, but they may have features of metabolic syndrome, including hypertension, dyslipidemia, and impaired glucose tolerance.
  • Patients may have reduced bone density and osteoporosis.
  • Patients are prone to adrenal insufficiency once the cortisol-secreting tumor is removed. This postoperative adrenal insufficiency is caused by corticotropin suppression and adrenal cortical atrophy of the contralateral adrenal gland (see Image 3).
  • Because urinary free cortisol levels may be within the reference range, a 1-mg overnight dexamethasone suppression test is needed to diagnose subclinical Cushing syndrome.
• The most important hormonally silent AA is pheochromocytoma.
• • They are present in approximately 1 in 1000 autopsies.
  • If the prevalence of AAs is 10-100 in 1000, then 1-10% of AIs are pheochromocytomas (see Image 4).
  • Pheochromocytomas should be considered in all AA cases because they are more common than previously thought, the diagnosis is often overlooked, and a failure to recognize them may lead to patient death.
  • A 24-hour urine catecholamines and metabolites evaluation remains a good test for the diagnosis of pheochromocytoma, but it is not as sensitive as free metanephrine testing, which is available in laboratories around the United States.
  • A 1981 series by Sutton et al reported that less than one quarter of pheochromocytomas found postmortem were diagnosed antemortem. Retrospective analysis found that more than 90% of these patients had characteristic symptoms suggesting the unrecognized tumors were not silent. Many of the patients died of causes possibly related to the pheochromocytoma. Approximately 29% died unexpectedly during surgery, 27% died from cardiovascular causes, and 17% died from cerebrovascular causes.
  • Assume all AAs have a pheochromocytoma until proven otherwise, especially when paroxysmal hyperadrenergic symptoms are present.
  • Exclude the presence of pheochromocytoma prior to performing a fine-needle aspiration (FNA) biopsy on the AM.
• Primary hyperaldosteronism is a less compelling, but nevertheless important, diagnosis.
• • Surgical intervention can cure the hypertension and hypokalemia.
  • The test of choice is an upright plasma aldosterone–to–renin ratio. A plasma aldosterone concentration–to–plasma renin activity ratio greater than 30 and a plasma aldosterone concentration of greater than 0.5 nmol/L (18 ng/dL) is suggestive of primary aldosteronism.
  • Hyperaldosteronism is usually identified by suppressed upright plasma renin levels and concomitant elevated plasma aldosterone levels.
• Other secreted hormones can include estrogens, androgens, and 17-hydroxyprogesterone.
• • They are associated with AAs, carcinomas, and hyperplasia.
  • They often manifest clinically and therefore do not require presumptive screening.

Imaging Studies

• CT scanning is preferred because it is more cost-effective than MRI to delineate size, shape, and appearance. A smooth homogeneous lesion smaller than 4 cm with a low attenuation value (Hounsfield units) is usually benign. A larger inhomogeneous lesion with irregular borders and a higher attenuation score should be considered for malignancy.
• MRI is as effective as CT scanning for distinguishing benign from malignant lesions and is superior for detecting pheochromocytomas. A benign adenoma has a T2-weighted intensity similar to liver tissue.
• Plain radiography, tomography, and ultrasonography are less sensitive and are used less frequently since the advent of CT scanning and MRI.
• Other scanning techniques include iodine I 131 metaiodobenzyl guanidine, for pheochromocytoma; iodine I 131-6-b-iodomethylnorcholesterol (NP-59 cholesterol), for adrenocortical lesions; and positron emission tomography; however, these test are not widely available and data on their clinical usefulness is insufficient.
• The following are features of pheochromocytomas:
• • They vary in size, consistency, and margins.
  • They can be bilateral.
  • They are strongly enhanced with contrast.
  • They show high signal intensity on T2-weighted images, owing to their vascularity.
• The following are features of adrenal carcinomas:
• • Adrenal carcinomas are often larger than 6 cm in diameter, with an irregular margin.
  • Adrenal carcinomas demonstrate a soft tissue inhomogeneous density on CT scans, which enhances with contrast.
  • Adrenal carcinomas are unilateral, sometimes with local invasion and lymphadenopathy and metastases.
  • Adrenal cortical carcinomas have an intermediate increased intensity on T2-weighted MRIs.
  • Myelolipomas show characteristic images of fat.
  • Hemorrhage shows characteristic images of blood.
• The following are features of Bilateral AMs:
• • Bilateral AMs should always raise the possibility of hemorrhage, especially in patients with coagulopathies or those on anticoagulant therapy.
  • Clinical symptoms include flank pain, nausea and vomiting, fever, and hypotension.
  • Diagnosis can be made with a rapid corticotropin stimulation test demonstrating decreased cortisol reserve.
• Bilateral AMs usually suggest certain systemic diseases that can produce adrenal insufficiency. They should be recognized early.
• • Fungal or tuberculosis infection may be present.
  • Granulomatous diseases (eg, histoplasmosis, tuberculosis) are characteristically homogeneous and may show calcifications.
  • Most metastatic disease to the adrenal gland is unilateral, but lymphoma may be bilateral and can cause adrenal insufficiency.
  • A 21-hydroxylase deficiency can produce unilateral AMs, but bilateral AMs are more common. To recognize this, measure the level of corticotropin-stimulated plasma 17-hydroxyprogesterone.
  • In a patient with primary hyperaldosteronism, bilateral AIs suggest bilateral adrenal hyperaldosteronism (idiopathic hyperaldosteronism). Confirm this by adrenal venous sampling to demonstrate bilateral plasma aldosterone secretion.
  • Long-standing, corticotropin-dependent Cushing syndrome may result in large AMs.
  • Another very rare cause of Cushing syndrome is adrenal-dependent macronodular hyperplasia associated with extremely large adrenal glands.

Procedures

• Adrenal FNA helps identify metastatic, systemic, and hemorrhagic disease of the adrenal glands.
• • It cannot distinguish between benign and malignant primary adrenal tumors.
  • It should be used only when AMs cannot be diagnosed clinically or hormonally.
  • Use CT scanning to guide a 23- or 25-gauge needle into the left or right adrenal gland.
  • If a metastatic lesion is found, initiate a search for the primary cancer.
  • If adrenal tissue is found, consider surgical removal.
  • Pheochromocytoma should always be excluded before performing FNA biopsy to avoid the potential for a hypertensive crisis.

Histologic Findings

Findings are based on the AM cell type.

TREATMENT

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Medical Care

See Image 5 for the proper medical approach.

• Adrenal insufficiency
• • Adrenal insufficiency should be the first consideration, especially with bilateral AMs.
  • A corticotropin test with 60-minute cortisol levels helps rule out the diagnosis.
  • If found, suspect granulomatous disease, hemorrhage, or lymphoma.
  • A 21-hydroxylase deficiency can also be diagnosed with a 60-minute post-corticotropin plasma 17-hydroxyprogesterone level.
• Hormonal excess
• • Use the 1-mg overnight dexamethasone suppression test, urinary free cortisol test, a urinary metanephrine–to–creatinine ratio, and a renin-to-aldosterone ratio.
  • If found, surgical removal is usually indicated.
  • Exceptions that do not warrant surgery include bilateral adrenal diseases such as corticotropin-dependent Cushing disease or bilateral hyperaldosteronism.
• If no hormonal excess is found and the corticotropin test results were unremarkable, FNA helps distinguish between adrenal and metastatic disease.
• • Metastatic disease is managed according to the type of primary cancer.
  • Adrenal disease should be removed if the diameter is greater than 6 cm. Otherwise, follow up with repeat CT scans at periodic intervals.

Surgical Care

• No randomized trials have compared laparotomy versus laparoscopic adrenalectomy; however, abdominal laparotomy is preferred for bilateral disease and pheochromocytoma.
• Fiberoptic laparoscopy is used for visualization, biopsy, and removal.
• A transthoracic approach is faster than fiberoptic laparoscopy but has a longer postoperative recovery period.
• Other experimental approaches, including a laparoscopic robot and augmented-reality visualization of the surgical field, have been described.

Consultations

An endocrinologist should be consulted to review the results of endocrine testing.

Diet

No specific diet recommendations are necessary.

Activity

No activity restrictions are necessary.

MEDICATION

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No specific medical therapy is required except treating the underlying disease.

FOLLOW-UP

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Complications

• For patients who do not have an adrenalectomy, follow-up is designed to detect interval changes in tumor size or the development of hormonal overproduction. Most adrenal lesions remain unchanged or decrease in size, whereas, 5-25% enlarge. Repeat CT scanning at 6-12 months is recommended, and, for lesions that do not increase in size, further testing is generally not warranted.
• Hypercortisolism (especially subclinical) is the most likely hormonal disorder to develop in the follow-up period and is subclinical in most cases. Primary hyperaldosteronism or catecholamine excess is rarely observed during follow up.
• Overnight 1-mg dexamethasone suppression testing, a renin-to-aldosterone ratio, and urinary catecholamine and metabolite measurements can be performed yearly or more frequently if clinically indicated. After several years, this testing can probably be discontinued.
• Adrenal insufficiency may occur with bilateral adrenal disease such as lymphoma or hemorrhage. Hypocortisolism may also occur as a result of corticotropin deficiency from a cortisol-secreting adenoma that is causing contralateral adrenal atrophy. The postoperative course for these patients is prolonged physiologic cortisol replacement.

Prognosis

• Generally, the prognosis is excellent, but it depends on the type of underlying adrenal disease. Patients with a previous history of cancer have a clinical course dictated by the primary tumor. Patients with adrenal cortical carcinomas have poor clinical outcomes, usually 2- to 5-year 50% overall survival rate.

Patient Education

• If pertinent, patients should know the signs and symptoms of adrenal insufficiency. Clinical clues include nausea, abdominal pain, fever, and diarrhea.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Pheochromocytomas should be considered in all AA cases because they are more common than previously thought, the diagnosis is often overlooked, and a failure to recognize them may lead to patient death.

MULTIMEDIA

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Media file 1:  Characteristics of adrenal masses and their malignant potential.
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Media file 2:  Differential diagnosis of adrenal mass
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Media file 3:  Pituitary-adrenal axis and cortisol-secreting adrenal mass.
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Media file 4:  Adrenal incidentaloma and disease type.
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Media file 5:  Diagnostic approach to adrenal incidentalomas.
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Media file 6:  Left adrenal mass discovered incidentally.
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Media file 7:  Close-up of the left adrenal incidentaloma from Image 6.
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Media file 8:  Left adrenal mass.
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Media type:  CT

REFERENCES

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Article Last Updated: Sep 11, 2007