Adrenal adenomas are benign neoplasms of the adrenal cortex. Adrenal adenomas are the most common cause of incidentally found adrenal tumors known as “adrenal incidentalomas.” Adrenal adenomas can be either hormonally active or inactive. These tumors are usually detected incidentally on imaging done for unrelated reasons and only in some cases do patients present with symptoms and/or features of hormonal abnormalities, most commonly overproduction of an adrenal hormone.
There are specific genetic mutations associated with hormonally active and inactive adrenal adenomas. However, the exact pathogenesis is not entirely clear.
Mutations of CTNNB1 genes which provide instructions for making beta-catenin (Wnt/beta-catenin pathway) is associated with the larger and non-secreting adrenocortical adenomas.
The mutations associated with cortisol-producing adrenal nodules include PRKACA (Cortisol Producing Adenoma) GNAS1 (McCune Albright syndrome), MENIN (multiple endocrine neoplasm type 1) and ARMC5 (hereditary bilateral adrenal adenoma).
The reported prevalence of adrenal incidentaloma varies depending on the criteria used. Based on CT scan findings, the reports of the prevalence of adrenal incidentalomas has been between 0.35% to 1.9%. However, an autopsy series reported a prevalence of 2.3%. Approximately 54% of adrenal incidentalomas are adrenal adenomas. Adrenal adenomas more commonly present in women (55%) compared to men (45%). The mean age for diagnosis is 57 years (range 16 to 83 years). Fifteen percent of adrenal incidentalomas show hypersecretion of hormones. The reported prevalence of hypercortisolism is between 1% to 29% (average 9%), hyperaldosteronism 1.5% to 3.3%, and pheochromocytoma 1.5% to 11%. Rarely, a patient can have bilateral adenomas, and in that case, other causes of bilateral adrenal masses should be considered such as metastatic disease, congenital adrenal hyperplasia, lymphoma, infections, hemorrhage and infiltrative conditions of the adrenal glands.
Non-secreting adrenal adenomas, or the ones that secrete low levels of hormones, are usually asymptomatic and discovered incidentally on abdominal imaging. The glucocorticoid producing adrenal tumors can present with the symptoms and signs of Cushing syndrome including obesity, hypertension, hyperglycemia, fatigue, depression, menstrual irregularities, proximal muscle weakness, acne, facial plethora, striae, fractures, and osteopenia. Aldosterone-secreting tumors may present with hypertension (quite frequently resistant hypertension with uncontrolled blood pressure despite the use of three or more antihypertensive medications of different classes), muscle weakness, hypokalemia, hypomagnesemia or hypernatremia.
There are two main goals in the evaluation of adrenal tumors. The first is to differentiate between benign and malignant masses and the second goal is to assess if the tumors are producing excessive hormones.
CT scan is the imaging of choice for evaluation of adrenal tumors. Adrenal tumor size greater than 4.0 cm has high sensitivity for adrenal cancer. Adrenal lesions which exhibit less than 10 HU (Hounsfield units) on non-contrast CT scan strongly suggest a benign adenoma. Some benign adenomas may have higher than 10 HU. Delayed contrast-enhanced CT scan may help to differentiate them from malignant lesions. MRI is an alternative to the CT scan for evaluation of adrenal tumors, but it is more expensive than CT scan.
Fine-needle aspiration biopsy of adrenal tumors is rarely necessary for select patients with single adrenal lesion who have a history of non-adrenal malignancy without evidence of other metastasis. In these cases, a pheochromocytoma needs to be ruled out first before any invasive procedure takes place.
All patients with adrenal adenoma should be investigated for Cushing syndrome, and pheochromocytoma and patients with hypertension should additionally get investigation for hyperaldosteronism.
The initial test to diagnose Cushing syndrome is a low dose (1mg) dexamethasone suppression test. A plasma cortisol level of less than 1.8 mcg/dL after the overnight administration of 1mg dexamethasone has the best negative predictive value for Cushing syndrome. An abnormal test is confirmed with 24-hour urine free cortisol collection and a plasma ACTH level. A four-fold elevation of 24-hour urine cortisol level is diagnostic of Cushing syndrome.
Twenty-four-hour urinary fractionated metanephrines, or plasma fractionated metanephrines, are measured to assess for pheochromocytoma.
Plasma aldosterone level and plasma renin activity measurements are indicated in patients with adrenal adenoma who have hypertension. In patients with plasma aldosterone concentration greater than 15ng/dL and aldosterone to plasma renin activity over 20, the diagnosis is confirmed by demonstrating a lack of aldosterone suppressibility with sodium loading. In patients over 40 years of age, a selective adrenal vein sampling is indicated for localization purposes before surgery.
Adrenal tumors that are more than 4cm in size, hormonally indeterminate, or suspected to be malignant receive treatment with adrenalectomy. Benign appearing on imaging, less than 4 cm in size adrenal adenomas which are hormonally active on biochemical testing (Cushing syndrome, hyperaldosteronism, and pheochromocytoma) are treated with adrenalectomy as well. There is no long-term prospective data available to choose between medical and surgical treatment for patients with subclinical Cushing syndrome.
Patients with hyperaldosteronism who are not good surgical candidates due to advanced age or comorbidities, or the patients who refuse surgery, must be treated with aldosterone antagonists such as spironolactone or eplerenone.
Hormonally inactive adenomas are initially managed by reimaging in 3 to 6 months, then annually for 1 to 2 years, and they should also have repeat hormonal assessment once a year for 5 years. If the mass grows more than 1 cm or becomes hormonally active, then adrenalectomy is recommended.
The differential diagnosis include:
The long-term prognosis of patients with adrenal adenomas is excellent. Non-functioning adrenal adenomas rarely need treatment. Adrenal incidentalomas with no excessive hormone production have a risk of becoming hormonally active of 17%, 29% and 47% in 1, 2 and 5 years respectively. The risk of adrenal adenoma transforming into adrenocortical carcinoma is extremely rare.
The complications associated with adrenal adenoma are usually due to the excess hormone production causing Cushing syndrome, virilization or hyperaldosteronism. Rarely, large adenomas may cause a local mass effect.
Patients with Cushing syndrome have suppressed hypophyseal pituitary axis (HPA) and should have glucocorticoids administered once adrenalectomy is done until the HPA has recovered which may take a few months.
Patients with hyperaldosteronism should receive mineralocorticoid receptor antagonists in preparation for adrenalectomy and also get repleted with potassium. Postoperatively, improvement of blood pressure may take a few weeks to months.
Adrenal adenomas are not predictable or preventable. Patients should be advised to follow up with endocrinology specialists for further work up any time that there are abnormal findings on an imaging study, even if the findings are irrelevant to the initial problem that prompted to the specific testing.
Adrenal adenomas are usually incidental discoveries, and they may cause significant anxiety among patients and physicians. It is vital to refer these patients to endocrinologists for definitive diagnosis and follow up. A multidisciplinary approach including primary care providers (nurse practitioners, physician assistants, and family doctors), endocrinologists, radiologists, and endocrine surgeons, along with nurses and pharmacists depending on the course of treatment, can provide the best outcomes. [Level V] Even in the case of hormonally inactive adrenal adenoma, long term follow up with imaging and hormonal assessment is recommended as these adenomas may grow in size or become active hormonally at a later time. (Level III)
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