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
By definition, an adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but may also represent conditions requiring therapeutic intervention (e.g. adrenocortical carcinoma, pheochromocytoma,
hormone-producing adenoma or metastasis). The purpose of this guideline is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with adrenal incidentalomas based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main
clinical questions crucial for the management of adrenal incidentaloma patients, addressing these four with systematic literature searches: (A) How to assess risk of malignancy?; (B) How to define and manage low-level autonomous cortisol secretion, formerly called ‘subclinical’ Cushing’s syndrome?; (C) Who should have surgical treatment and how should it be
performed?; (D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? Selected recommendations: (i) At the time of initial detection of an adrenal mass establishing whether the mass is benign or malignant is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. (ii) To
exclude cortisol excess, a 1 mg overnight dexamethasone suppression test should be performed (applying a cut-off value of serum cortisol ≤50 nmol/L (1.8 μg/dL)). (iii) For patients without clinical signs of overt Cushing’s syndrome but serum cortisol levels post 1 mg dexamethasone >138 nmol/L (>5 μg/dL), we propose the term ‘autonomous cortisol secretion’. (iv) All patients with ‘(possible) autonomous cortisol’ secretion should be screened for hypertension and type 2 diabetes mellitus, to ensure these are appropriately treated. (v) Surgical treatment should be considered in an individualized approach in patients with ‘autonomous cortisol secretion’ who also have comorbidities that are potentially related to cortisol excess. (vi) In principle, the appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. (vii) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. Furthermore, we offer recommendations for the follow-up of patients with adrenal incidentaloma who do not undergo adrenal surgery, for those with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal
masses and for young and elderly patients with adrenal incidentalomas.
Historical Perspective
In 1979, Korobkin et al. was the first to discover incidentaloma. In 1989, a large study at the Mayo Clinic found a 3.4% prevalence of adrenal incidentaloma.
Classification
Pathophysiology
The pathophysiology of adrenal incidentaloma depends on nature of the mass and its function. Incidentalomas are adrenal tumors that often discovered as an incidental finding. Malignancy is an uncommon cause of adrenal incidentaloma in patients without a known diagnosis of cancer. It may secrete cortisol. Cushing's syndrome is linked to hypercortisolism which can develop by excess ACTH secretion or excess cortisol secretion by adrenal glands. It may secrete catecholanines and in this case it is considered pheochromocytoma. Pheochromocytoma arises from chromaffin cells of the adrenal medulla and sympathetic ganglia. Malignant and benign pheochromocytomas share the same biochemical and histological features, the only difference is to have a distant spread or be locally invasive. 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 for the TP53 tumor suppressor gene in sporadic adrenocortical carcinoma. On gross pathology, adrenocortical adenoma is a well circumscribed, yellow tumour in the adrenal cortex, which is usually 2–5 cm in diameter. The color of 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 clinically inapparent adrenal masses 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
Screening
According to the European Society of Endocrinology Clinical Practice Guideline, screening for adrenal incidentaloma includes: family screening for patients with bilateral macronodular hyperplasia, patients with asymptomatic vertebral fractures, patients with possible autonomous cortisol secretion, 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
History and Symptoms
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: Paroxysmal attacks of hypertension, palpitation, diaphoresis, headache, pallor, and tremor. Primary hyperaldosteronism patients show hypertension and hypokalemia. Approximately 60 percent of adrenocortical carcinomas (ACCs) are sufficiently secretory to present clinical syndrome of hormone excess. Family history of Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and multiple endocrine neoplasia type 1 (MEN1).
Physical Examination
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 rapid strong equal pulse and high blood pressure. Jaundice, hyperpigmentation, telangiectasia, thinning of the skin and easy bruising may be found. Abdominal distention in patients with primary hyperparathyroidism associated constipation. A palpable abdominal mass in the lower abdominal quadrant. Hyporeflexia due to low potassium level in aldosternonma, proximal muscle weakness bilaterally, and bilateral tremors may be found also.
Laboratory Findings.
Laboratory findings consistent with the diagnosis of incidentaloma include an abnormal 1 mg overnight dexamethasone for subclinical 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 and UltraSound
X-ray
There are no x-ray findings associated with adrenal incidentaloma.
CT scan
Abdominal CT scan may be helpful in the diagnosis of [disease name]. Differentiation between benign and malignant incidentaloma is important. Malignancy is suggested on CT by a large diameter more than 6 cms, 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 malignantlesions 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 malignancybecause 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 include 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 include 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 [disease or malignancy]. Adrenalectomy for patients with aldosteronomas, pheochromocytoma, cortisol-secreting tumors, and adrenalincidentalomas 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 prevention of incidentaloma.
Secondary Prevention
Effective measures for the secondary prevention of adrenal incidentaloma include annual biochemical follow-up for up to 5 yr, 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 CTstudy in 3–6 months and then yearly for 2 yr.