Incidentaloma overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]
Overview
Adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for a suspected adrenal disease. Malignancy is an uncommon cause of adrenal incidentaloma. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, although, they may secrete cortisol, catecholamines or aldosterone. Common causes of incidentaloma include adenoma, carcinoma, pheochromocytoma, congenital adrenal hyperplasia, myelolipoma, and hemangioma. If left untreated, patients with adrenal incidentaloma may progress to develop Dyslipidemia, Osteoporosis, Hyperglycemia, Malignant hypertension, Intracranial hemorrhage, Acute coronary syndrome, Aortic dissection, malignant transformation, and metastasis. Prevalence of adrenal incidentaloma is 2% in autopsy studies and 3% in radiological studies. It may present with symptoms that are mainly subclinical such as subclinical Cushing's syndrome which includes diabetes, and a high incidence of vertebral fractures, dyslipidemia, impaired glucose tolerance or type 2 diabetes mellitus, and evidence of atherosclerosis. Pheochromocytoma symptoms and signs are paroxysmal attacks of hypertension, palpitations, diaphoresis, headache, pallor, and tremor. Primary hyperaldosteronism patients show hypertension and hypokalemia. Abdominal CT scan may be helpful in the diagnosis of adrenal incidentaloma to the differentiation between benign and malignant incidentaloma. Malignancy is suggested on CT by a large diameter more than 6 cm, irregular border, inhomogeneity, a “washout” of contrast after 15 min of less than 40%, and calcifications. MRI has advantages in certain clinical situations. The advantages of MRI over CT are its lack of radiation exposure, lack of iodine-based contrast media and its superior tissue contrast resolution. Surgery is the mainstay of treatment for incidentalomas. Adrenalectomy for patients with hyperaldosteronism, pheochromocytoma, cortisol-secreting tumors, and adrenal incidentalomas is safe and effective.
Historical Perspective
In 1979, incidentaloma was first described by Korobkin et al. In 1989, a large study at the Mayo Clinic found the prevalence of adrenal incidentaloma to be 3400 per 100,000 persons.
Classification
Adrenal incidentaloma may be classified as functioning (secreting) or non-functioning incidentaloma. Adrenal incidentaloma may also be classified by the nature into benign masses or malignant masses.
Pathophysiology
The pathophysiology of adrenal incidentaloma depends on nature and function of the mass. Incidentalomas are mostly adrenal tumors that are often discovered as an incidental finding. Malignancy is an uncommon cause of adrenal incidentaloma in patients without a known diagnosis of cancer. An adrenal incidentaloma may secrete cortisol. Cushing's syndrome is linked to hypercortisolism which can develop by excess ACTH secretion or excess cortisol secretion by adrenal glands. An adrenal incidentaloma may secrete catecholamines and in such a case it is considered a pheochromocytoma. It may be sporadic, but some occur as a component of hereditary cancer syndromes such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and Multiple endocrine neoplasia type 1. Genetic base of sporadic incidentaloma is mutations in TP53 gene, located on chromosome 17p13. A role of the TP53 tumor suppressor gene in sporadic adrenocortical carcinoma has also been studied. On gross pathology, adrenocortical adenoma is a yellow, well circumscribed tumor in the adrenal cortex, which is usually 2–5 cm in diameter. The color of the tumor, as with adrenal cortex as a whole, is due to the stored lipid (mainly cholesterol), from which the cortical hormones are synthesized.
Causes
Common causes of incidentaloma include adenoma, carcinoma, pheochromocytoma, congenital adrenal hyperplasia, massive macronodular adrenal disease, and nodular variant of Cushing’s disease. Less Common Causes include myelolipoma, neuroblastoma, ganglioneuroma, hemangioma.
Differentiating adrenal incidentaloma from Other Diseases
Adrenal incidentaloma must be differentiated from other diseases that cause adrenal masses such as adrenal adenoma, adrenocortical carcinoma, Cushing's syndrome, pheochromocytoma, and metastasis.
Epidemiology and Demographics
Prevalence of adrenal masses which are not apparent clinically is around 2% in autopsy studies. Radiological studies report a frequency of around 3%. The prevalence of adrenal incidentalomas increases with age. The prevalence of adrenal incidentaloma is higher in older patients 10%. There is no racial or gender predilection to incidentaloma.
Risk Factors
Most adrenocortical carcinomas are sporadic, but some occur as a component of hereditary cancer syndromes such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and multiple endocrine neoplasia type 1(MEN1). Genetic basis of sporadic incidentaloma include TP53 gene. A role for the TP53 tumor suppressor gene in sporadic ACCs is suggested by the frequent finding of loss of heterozygosity (LOH) at the 17p13 locus in sporadic ACCs. Another chromosomal locus that is strongly implicated in the pathogenesis of ACC is 11p, the area of abnormality in Beckwith-Wiedemann syndrome and the site of the insulin-like growth factor-2 (IGF-2) gene.
Screening
According to the European Society of Endocrinology Clinical Practice Guideline, screening for adrenal incidentaloma includes: family screening for patients with bilateral macro-nodular hyperplasia, patients with asymptomatic vertebral fractures, patients with possible autonomous cortisol secretion, and patients with a hereditary syndrome leading to adrenal tumors. Screening test include 24-hour urine fractionated metanephrines for pheochromocytoma, 24-hour urinary free cortisol for patients with symptoms of Cushing's syndrome, and plasma aldosterone concentration, plasma renin activity for patients with primary aldosteronism.
Natural History, Complications, and Prognosis
If left untreated, patients with adrenal incidentaloma may progress to develop dyslipidemia, osteoporosis, hyperglycemia, malignant hypertension, intracranial hemorrhage, acute coronary syndrome, aortic dissection, malignant transformation, and metastasis. Prognosis is usually good in benign adrenal incidentalomas, death is not directly related to the adrenal mass, but to cardiovascular accidents, malignancy, and chronic disorders, as observed in the general population. Adrenocortical carcinoma (ACC) carries a poor prognosis and is unlike most tumors of the adrenal cortex, which are benign (adenomas) and only occasionally cause Cushing's syndrome.
Diagnosis
Diagnostic Criteria
There are no definitive diagnostic criteria for adrenal incidentaloma management but there are guidelines to diagnose and treat the mass according to Endocrine Society. Radiological evaluation including non-contrast CT attenuation value expressed in Hounsfield unit (HU) is the best tool to differentiate between benign and malignant adrenal masses. All patients should undergo hormonal evaluation for subclinical Cushing's syndrome and pheochromocytoma, and those with hypertension should also be evaluated for primary hyperaldosteronism.
History and Symptoms
Sub-clinical Cushing's syndrome which includes diabetes, and a high incidence of vertebral fractures, dyslipidemia, impaired glucose tolerance or type 2 diabetes mellitus, and evidence of atherosclerosis. Pheochromocytoma: Paroxysmal attacks of hypertension, palpitations, diaphoresis, headache, pallor, and tremor. Primary hyperaldosteronism patients show hypertension and hypokalemia. Approximately 60 percent of adrenocortical carcinomas (ACC) are sufficiently secretory to present clinical syndrome of hormone excess. The family history of Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and multiple endocrine neoplasia type 1 (MEN1).
Physical Examination
Most of patients will not show any special signs as the definition of adrenal incidentaloma means incidentaly discovered mass during imaging for ant other reasons. Some cases shows signs of subclinical Cushing's syndrome, pheochromocytoma, or hyperaldosteronism. Common physical examination findings of include patients may appear quite well if the disease is asymptomatic. Patients may appear tired, weak, diaphoretic and anxious. Tachypnea if malignant secondaries are found in the lung with a rapid strong equal pulse and high blood pressure. Jaundice, hyperpigmentation, Telangiectasia, thinning of the skin and easy bruising may be found. A palpable abdominal mass in the lower abdominal quadrant may be found. Hyporeflexia due to low potassium level in aldosternonma, Proximal muscle weakness bilaterally, and bilateral tremors may be found.
Laboratory Findings.
Laboratory findings consistent with the diagnosis of incidentaloma include an abnormal 1 mg over night dexamethasone for sub-clinical Cushing's syndrome that should be confirmed with 24-hour urinary free cortisol, serum ACTH concentration, and dehydroepiandrosterone sulfate (DHEAS). In patients with adrenal masses that have a probability for pheochromocytoma, routine measurement of 24-hour urinary fractionated metanephrines and catecholamines should be done. All patients with hypertension and an adrenal incidentaloma should be evaluated by measurements of plasma aldosterone concentration and plasma renin activity.
Electrocardiogram
On EKG, catecholamines secreting incidentaloma is characterized by the presence of sinus tachycardia and supraventricular tachycardia.
X-ray
There are no x-ray findings associated with adrenal incidentaloma.
CT scan
Abdominal CT scan may be helpful in the diagnosis of adrenal incidentaloma. Differentiation between benign and malignant incidentaloma is important. Malignancy is suggested on CT by a large diameter more than 6 cm, irregular border, inhomogeneity, a “washout” of contrast after 15 min of less than 40%, and calcifications. Contrast-enhanced washout CT utilizes the unique perfusion pattern of adenomas. Adenomas take up intravenous CT contrast rapidly, but also have a rapid loss of contrast – a phenomenon termed ‘contrast enhancement washout’. It is assumed that malignant adrenal lesions usually enhance rapidly but demonstrate a slower washout of contrast medium.
MRI
Adrenal MRI may be helpful in the diagnosis of incidentaloma. Findings on MRI suggestive of incidentaloma include mild enhancement and a rapid washout of contrast, while malignant lesions show rapid and marked enhancement and a slower washout pattern. MRI has advantages in certain clinical situations. The advantages of MRI over CT are its lack of radiation exposure, lack of iodine-based contrast media and its superior tissue contrast resolution.
Other Imaging Findings
Findings on a Positron Emission Tomography (PET-CT) scan suggestive of/diagnostic of incidentaloma. Cancer cells have an increased requirement for glucose and take up more glucose and deoxyglucose than normal cells. standard uptake value (SUV) values have been utilized to differentiate between benign and malignant adrenal lesions. It may be helpful in the diagnosis of incidentaloma in selected patients; those with a history of malignancy or those in which CT densitometry or washout analysis is inconclusive or suspicious for malignancy because of their high sensitivity for detecting malignancy.
Other Diagnostic Studies
Fine-needle aspiration biopsy may be helpful in the diagnosis of incidentaloma. It can distinguish between an adrenal tumor and a metastatic tumor. In a patient with a known primary malignancy, performing a diagnostic CT-guided FNA biopsy may be indicated. The FNA biopsy of a pheochromocytoma may result in hemorrhage and hypertensive crisis. So, excluding pheochromocytoma with biochemical testing is necessary before any procedure.
Treatment
Medical Therapy
The mainstay of treatment for adrenal incidentaloma is surgery but preoperative medical management is needed for functional masses. Perioperative medical management of patients with subclinical Cushing's syndrome includes glucocorticoid therapy during surgery. Such patients can safely undergo surgical resection of their tumor and have their cortisol levels measured postoperatively. Preoperative medical management of patients with pheochromocytoma includes preoperative treatment to control hypertension during surgery and hypotension after it. Three medical regimens for preoperative management of pheochromocytoma: Combined alpha and beta-adrenergic blockers, calcium channel blockers, and Metyrosine. Preoperative medical management of patients with aldosteronoma include medical therapy with mineralocorticoid receptor antagonists should be reserved for those who are unable or unwilling to undergo surgery.
Surgery
Surgery is the mainstay of treatment for adrenal incidentaloma. Adrenalectomy for patients with hyperaldosteronism, pheochromocytoma, cortisol-secreting tumors, and adrenal incidentalomas is safe and effective. A reasonable strategy may be to consider adrenalectomy for younger patients and those with new onset or a worsening of underlying comorbidities such as diabetes mellitus, hypertension, obesity, or osteoporosis. All patients with documented pheochromocytoma and adrenocortical cancer should undergo prompt surgical intervention. Risk factors for complications during surgery include high plasma norepinephrine concentration and larger tumor size.
Primary Prevention
There is no established method for primary prevention of incidentaloma.
Secondary Prevention
Effective measures for the secondary prevention of adrenal incidentaloma include annual biochemical follow-up for up to 5 years, no routine follow-up of adrenal incidentalomas with a non-contrast attenuation value no greater than 10 HU. Patients with adrenal masses less than 4 cm in size and a non-contrast attenuation value more than 10 HU should have a repeat CT study in 3–6 months and then yearly for 2 years.