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Adrenal Adenoma
Introduction
Adrenal adenomas are benign neoplasms that originate from the adrenal cortex. Most adrenal adenomas are typically discovered incidentally during abdominal imaging, leading to the monicker “adrenal incidentaloma.” The significance of adrenal adenomas lies in their potential hormonal activity. Although many adrenal adenomas do not produce any hormones, these adenomas can overproduce adrenal cortical hormones.
The adrenal glands, situated superiorly to the kidneys, produce hormones. They consist of both medullary and cortical tissues. The adrenal medulla, which accounts for approximately 15% of the adrenal mass, responds to circulating dopamine during stressful situations by producing and releasing catecholamines as part of the sympathetic stress response.[1] The adrenal cortex can be subdivided into distinct regions known as the zona glomerulosa, zona fasciculata, and zona reticularis. Each zone is responsible for producing specific hormones, namely mineralocorticoids, glucocorticoids, and androgens, respectively.
When a mass is detected within the adrenal gland, either incidentally or due to symptoms, it is crucial to differentiate between benign and malignant masses and functional and nonfunctional masses. This comprehensive evaluation process is essential not only for accurate identification but also for excluding potentially life-threatening malignancies.
Adrenocortical carcinoma and pheochromocytoma represent potentially malignant masses that can occur in the adrenal glands. Although these tumors may exhibit hormonal activity, they differ from adenomas in their ability to expand and metastasize beyond the adrenal gland, potentially leading to metastasis.
Adrenal adenomas, in contrast, do not possess the potential to become malignant. Adenomas that do not produce hormones (nonfunctional) and are small in size do not require additional treatment. However, when an adenoma produces adrenal cortical hormones, it often involves cortisol or aldosterone. Androgen-producing adenomas are extremely rare and are more often associated with adrenocortical carcinoma.[2][3] Excess cortisol production can be classified based on the amount of hormone produced and the associated symptoms. Adenomas that produce cortisol associated with systemic symptoms are considered typical presentations of Cushing syndrome. On the other hand, adenomas that produce cortisol in smaller quantities, without obvious signs of hypercortisolism, are referred to as mild autonomous cortisol secretion (MACS) tumors. The treatment approach for adrenal adenomas involves managing the hormonal imbalance and considering surgical correction.
Etiology
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Etiology
Genetic understanding of adrenal adenomas, similar to many other areas of medicine, is evolving rapidly. Certain genetic mutations have been linked to both hormonally active and hormonally inactive adrenal adenomas. However, the precise mechanisms underlying their pathogenesis remain unclear.[4]
Mutations in the CTNNB1 genes, which provide instructions for making beta-catenin (Wnt/beta-catenin pathway), have been associated with the development of larger, nonsecreting adrenocortical adenomas.[5]
The mutations associated with macronodular cortisol-producing adrenal nodules include PRKACA (associated with cortisol-producing adenoma),[6][7] GNAS1 (linked to McCune-Albright syndrome),[8] MENIN (related to multiple endocrine neoplasm type 1), ARMC5 (associated with primary bilateral macronodular adrenal hyperplasia), APC (associated with primary bilateral macronodular adrenal hyperplasia), and FH (related to primary bilateral macronodular adrenal hyperplasia).[9][10] Micronodular cortisol-producing adrenal hyperplasias result from PRKAR1A (associated with primary pigmented nodular adrenocortical disease from altered Carney complex), PDE11A (linked to isolated micronodular adrenocortical disease), and PDE8B (also associated with isolated micronodular adrenocortical disease).[10]
The mutations associated with aldosterone-producing adrenal adenomas include KCNJ5, which accounts for approximately 40% of such cases.[11][10] In addition, mutations in ATP1A1, ATP2B3, CACNA1D, and CTNNB1 have also been associated with this condition.[12]
Epidemiology
The increasing utilization of computed tomography (CT) imaging has led to a higher frequency of reported cases of adrenal adenomas. The reported prevalence of adrenal incidentaloma varies depending on the criteria used. Based on CT findings, studies have reported that the prevalence of adrenal incidentalomas ranges between 0.35% and 1.9%. However, an autopsy series indicated a slightly higher prevalence of 2.3%.[13]
Adrenal adenomas account for approximately 54% to 75% of adrenal incidentalomas.[14] Although most studies indicate a higher prevalence of adrenal adenomas in females than males,[15][16] there are a few cases of male predominance, notably in a large Korean study.[17] The mean age for diagnosis is 57, with reported cases spanning a wide range of ages from 16 to 83.[15]
Approximately 15% of adrenal incidentalomas exhibit hypersecretion of hormones. The reported prevalence of hypercortisolism ranges from 1% to 29%, hyperaldosteronism from 1.5% to 3.3%, and pheochromocytoma from 1.5% to 11%.[13][18]
In rare cases, a patient may present with bilateral adrenal nodules. In such instances, it is essential to consider other potential causes of bilateral adrenal masses, including metastatic disease, congenital adrenal hyperplasia, lymphoma, infections, hemorrhage, and infiltrative conditions affecting the adrenal glands.
History and Physical
Nonsecreting adrenal adenomas or those with low hormone production typically do not cause symptoms and are often discovered incidentally during abdominal imaging. However, adrenal adenomas that produce excessive glucocorticoids can lead to the clinical manifestations of Cushing syndrome. These symptoms may include obesity, hypertension, hyperglycemia, fatigue, depression, menstrual irregularities, proximal muscle weakness, acne, facial plethora, purple striae, fractures, and osteopenia.
Aldosterone-secreting tumors commonly manifest as either treatment-resistant hypertension, which is characterized by uncontrolled blood pressure despite the use of 3 or more antihypertensive medications from different classes, or hypokalemia. Additional symptoms of hyperaldosteronism may include muscle weakness, hypomagnesemia, or hypernatremia. In cases where the adenoma produces aldosterone, the symptoms experienced by patients can vary based on their biological sex. Adult males typically exhibit minimal symptoms, mostly a reduction in the size of their testes. On the other hand, adult females are more affected by elevated androgen levels and may exhibit menstrual aberrancies, hirsutism, male-pattern baldness, and acne.
Evaluation
The evaluation of adrenal tumors primarily focuses on 2 key goals: the first goal is to distinguish between benign and malignant masses, whereas the second goal is to determine whether the tumors are hormonally active or nonfunctioning.[19]
After detecting an adrenal mass, an adrenal-dedicated CT scan or Magnetic Resonance Imaging (MRI) is the preferred imaging modality for evaluating adrenal adenomas.[20] Adrenal tumor size exceeding 4.0 cm has a high sensitivity for adrenal carcinoma.[21] In addition, adrenal lesions exhibiting less than 10 Hounsfield units (HU) on noncontrast CT imaging strongly indicate a benign adenoma.[22] Some benign adenomas may have higher than 10 HU values. In such cases, a delayed contrast-enhanced CT scan can aid in differentiating between benign and malignant lesions.[23][24]
A contrast medium absolute washout of more than 60% and a relative washout of more than 40% in delayed CT images have been reported to be highly sensitive and specific for diagnosing patients with adenomas compared to those with carcinomas, pheochromocytomas, or metastases.[25][26] However, a recent study has indicated that contrast washout has lower sensitivity and specificity for accurately distinguishing benign adenomas.[27] MRI can be used to evaluate adrenal masses as an alternative to CT imaging. MRI with chemical shift imaging has demonstrated high sensitivity and specificity in diagnosing adrenal adenomas.[24]
Before proceeding with dynamic hormonal testing specifically for adrenal adenomas, it is essential for all patients with an adrenal mass detected on imaging to undergo a comprehensive workup for pheochromocytoma. Pheochromocytoma can be challenging to definitively exclude based on imaging alone.[28]
After confirming the absence of malignancy and pheochromocytoma, it is important to evaluate every patient for excessive cortisol production, which can manifest as either Cushing syndrome or MACS. Although various laboratory modalities exist for testing excess cortisol levels, such as late-night salivary testing and 24-hour urinary cortisol, the preferred initial diagnostic test for Cushing syndrome and MACS is a low-dose of 1-mg dexamethasone suppression test. Patients should ingest a 1-mg dose of dexamethasone orally between 11 PM and 12 AM to perform the dexamethasone suppression test accurately. The following morning, between 8 AM and 9 AM, patients should undergo a scheduled fasting blood draw at a laboratory to measure their cortisol levels. This protocol ensures the proper timing and conditions for obtaining reliable test results.[29][30]
A plasma cortisol level of less than 1.8 mcg/dL following the overnight administration of low-dose dexamethasone provides the most reliable negative predictive value for hypercortisolism. However, to confirm a diagnosis of Cushing syndrome or MACS, an abnormal test result should be further confirmed using one of the additional excess cortisol tests mentioned previously. It is important to note that dexamethasone is hepatically metabolized in the liver through the CYP 3A4 system.[30] Before utilizing a low-dose dexamethasone suppression test for diagnosing cortisol excess, healthcare providers must verify that the patient is not taking any medications that induce or inhibit this pathway. In addition, certain medications, particularly estrogens, can increase the levels of cortisol-binding globulin, which can lead to artificially elevated cortisol levels.[31] In these patients, it is advisable to consider alternative methods for assessing excess cortisol. A measured dexamethasone level should be ordered simultaneously as the cortisol level is checked the following morning.
Patients with an adrenal adenoma and hypertension (with or without hypokalemia) should additionally be tested for primary hyperaldosteronism. The most reliable test for primary hyperaldosteronism is the aldosterone-plasma renin ratio (ARR).[32] ARR testing can be a complex process that involves several preparatory steps before testing. Patients should discontinue medications that impact aldosterone or renin levels, such as mineralocorticoid receptor antagonists and potassium-wasting diuretics, for at least 4 weeks (and potentially up to 6 weeks) before the test. It should also be noted that angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-2 agonist blockers, central alpha-2 agonists, and calcium channel blockers may be continued during this time. However, these medications may need to be held if the initial ARR testing is nondiagnostic and further ARR testing is deemed necessary. Other antihypertensives may be required to be initiated during the medication-free period to maintain proper blood pressure control. In the case of oral contraceptive use, collecting direct renin concentration instead of plasma renin activity can result in a false-positive ARR. Furthermore, patients should be advised to increase their sodium and potassium intake while abstaining from licorice products in their diet.
On the day of ARR testing, it is recommended that the patient has their aldosterone and renin levels tested approximately 2 hours after waking up. The patient should be seated in the laboratory for at least 5 to 15 minutes before the blood samples are collected for testing. Samples must be collected with utmost care to prevent hemolysis, and they should be stored at room temperature to avoid the conversion of inactive renin to its active form. In cases where the plasma renin activity of the patient is suppressed (defined as the plasma aldosterone concentration exceeding 15 ng/dL and ARR over 20 ng/mL/h), the diagnosis of primary hyperaldosteronism is confirmed by demonstrating a lack of aldosterone suppressibility upon sodium loading.[33]
Although confirmatory testing is recommended, there is no universally accepted gold standard testing modality for diagnosing primary hyperaldosteronism. However, several commonly accepted confirmatory tests include oral sodium loading, saline infusion, fludrocortisone suppression, and captopril challenge tests. Adrenal vein sampling is recommended only when a patient is willing to consider surgical treatment for primary hyperaldosteronism. Its main purpose is to differentiate between unilateral hyperaldosteronism and bilateral adrenal disease. This is particularly important in patients with bilateral adrenal nodules detected on imaging or unilateral nodules in patients older than 35.[34]
Fine-needle aspiration (FNA) biopsy of adrenal tumors is generally unnecessary for patients with a single adrenal lesion and a history of nonadrenal malignancy as long as there is no evidence of metastasis. However, an adrenal biopsy may be considered in cases of indeterminate imaging where additional information is needed for proper management. FNA is not typically indicated for indeterminate adrenal lesions as it cannot differentiate between benign cortical mass and adrenal carcinoma. It also carries the risk of needle-track seeding of possibly malignant cells.[35] In cases where the potential benefit of performing a biopsy outweighs the associated risks, it is essential to rule out the presence of a pheochromocytoma before proceeding with any invasive procedure. This is crucial because performing a biopsy in the presence of pheochromocytoma can lead to an acute exacerbation of hypertension, tachycardia, and tremors.[22]
Treatment / Management
Unilateral adrenalectomy is the preferred treatment for adenomas larger than 4 cm, which are suspected to be malignant, or any hormonally active adenomas that show biochemical evidence of Cushing syndrome or primary hyperaldosteronism. Although adrenalectomy has not been demonstrated to be superior to medical management in cases of MACS, leading adrenal experts have suggested considering adrenalectomy for younger patients with MACS who experience worsening diabetes mellitus, hypertension, or osteoporosis.[36] Discussions and shared decision-making among patients and their healthcare providers are essential in determining the most suitable treatment modality.
Medical management of hormone-secreting adenomas is typically reserved for unsuitable candidates for surgery due to advanced age, serious comorbidities, or patients who decline surgical correction. In such cases, the primary goal is to alleviate the symptoms and block hormone receptors. For excessive cortisol secretion, mifepristone, a glucocorticoid receptor antagonist, can be implemented.[37] Ketoconazole can also be a potential option due to its direct effects on the adrenal glands.[37] Patients with hyperaldosteronism should be treated with mineralocorticoid receptor antagonists such as spironolactone or eplerenone.
Hormonally inactive adenomas are initially managed by conducting reimaging in 3 to 6 months, followed by annual imaging for 1 to 2 years. In addition, repeat hormonal assessments should be performed annually for 5 years. If the mass exhibits growth exceeding 1 cm or becomes hormonally active, adrenalectomy is recommended.[38]
Differential Diagnosis
The differential diagnoses include the following:
- Carcinoma
- Metastasis
- Nodular hyperplasia
- Cysts
- Myelolipoma
- Angiomyolipoma
- Hemangioma
- Pheochromocytoma
- Hamartoma
- Granulomatosis
Prognosis
The long-term prognosis of patients with adrenal adenomas is typically excellent. Nonfunctioning adrenal adenomas often do not require treatment. Adrenal incidentalomas without excessive hormone production have a risk of becoming hormonally active, estimated at 17%, 29%, and 47% within 1, 2, or 5 years, respectively.[39] However, the transformation of an adrenal adenoma into adrenocortical carcinoma is an extremely rare occurrence.
Complications
Cushing syndrome resulting from a cortisol-producing adrenal adenoma has been associated with a wide range of complications, with metabolic and cardiovascular disorders being particularly noteworthy.[4][40] The adverse effects are primarily attributed to the mechanism of increased insulin resistance caused by hypercortisolism, leading to a subsequent increase in abdominal adiposity.[41] Over the past several years, these complications have also been reported in adrenal adenomas with MACS.[42][43] In addition, the overproduction of cortisol inhibits the hypothalamic-pituitary-thyroid axis and stimulates somatostatin, which reduces the levels of T3/T4 hormones.[44] The same mechanism of action is also responsible for decreased growth hormone production in these patients.[45]
The most common complication associated with aldosterone-producing adenomas is uncontrollable hypertension. Without proper diagnosis and treatment, primary hyperaldosteronism can result in sodium and water retention at the nephron level, leading to complications such as fluid overload, heart failure, atrial fibrillation, and myocardial infarction.[46]
In rare cases, nonfunctioning adrenal adenomas can lead to mass effects. However, it is essential to note that most lesions large enough to cause mass effects are typically malignant.[21]
Postoperative and Rehabilitation Care
The decision to proceed with surgical correction is made following extensive discussions between the patient and their healthcare provider, considering the potential complications of the disease and the risks associated with surgery. In cases where thorough testing confirms that the adenoma does not produce any hormones, surgical correction is not required. However, for unilateral adenomas with hormonal activity, adrenalectomy is considered the gold standard treatment.[47][48][49]
Due to the excessive production of cortisol in Cushing syndrome and MACS, patients experience chronic suppression of the hypophyseal-pituitary-adrenal (HPA) axis. Following adrenalectomy, patients will need exogenous glucocorticoid supplementation during the recovery of the HPA axis, which may take several months. According to the guidelines of the Endocrine Society, it is recommended to initiate hydrocortisone supplementation on the first day after surgery, starting at a dosage of 10 to 12 mg/m2 per day, divided into 2 to 3 dosages throughout the day.[48] Although twice-daily dosing has been the standard approach for glucocorticoid replacement, recent studies have shown that administering glucocorticoids 3 times daily can help reduce hypercortisolemia in the morning and hypocortisolemia in the evening.[50] In cases where patients are unable to tolerate multiple daily doses, an alternative option is to use prednisolone at a daily dosage of 3 to 5 mg.[51] However, it should be noted that even with postoperative glucocorticoid replacement, many patients may still develop symptoms of adrenal insufficiency.
Patients should inform their physicians if they develop symptoms such as fatigue, weight loss, myalgias, weakness, abdominal pain, postural hypotension, or new atypical depressive symptoms.[52][53] In addition, patients should be educated on stress-dosing for sick days while receiving glucocorticoid replacement therapy. Furthermore, it is important to educate patients receiving glucocorticoid replacement therapy about stress-dosing during sick days. As a general guideline, patients should be advised to double their daily dose of glucocorticoid when encountering minor illnesses.[51]
Following the surgery, it is recommended to reassess the patient's HPA axis at intervals of 3 to 6 months. The assessment includes measuring cortisol levels at 8 AM (before the morning dosage of glucocorticoid) and performing ACTH (adrenocorticotropic hormone) stimulation testing when the morning cortisol level exceeds 7.4 mcg/dL.[48] The recovery of the HPA axis is typically confirmed when the morning cortisol level exceeds 18 mcg/dL, with or without ACTH stimulation. After the HPA axis has normalized, glucocorticoids may be tapered at a rate determined by the healthcare provider based on the individual patient's response.
Similar to hypercortisolism, unilateral adrenalectomy for hyperaldosteronism can reveal contralateral adrenal suppression. Patients who undergo unilateral adrenalectomy for an aldosterone-producing adenoma should have their aldosterone and renin levels tested on the same day as the surgery to monitor the response and ensure appropriate management.[32] However, renin levels may not rise immediately following the adrenalectomy procedure. Therefore, monitoring other factors such as aldosterone levels and blood pressure concurrently is necessary.
In terms of postoperative management, potassium replacement and the use of spironolactone may be discontinued immediately following the surgery. Antihypertensive medications should be resumed if the patient continues to experience hypertension after undergoing adrenalectomy. Although the patient may require fewer medications to manage their blood pressure, it is noteworthy that the improvement in blood pressure may take several weeks to months, and in rare cases, it may even take up to 1 year to achieve optimal control.
Consultations
The management of adrenal adenomas requires close coordination among professionals from various medical fields. Effective collaboration among the primary team, which comprises physicians, nurse practitioners, physician assistants, nurses, and pharmacists, is of paramount importance. Given the extensive hormonal workup involved in the diagnosis and management of adrenal adenomas, it is advisable to refer patients to an endocrinologist for specialized care. In cases where additional intensive testing, such as adrenal vein sampling, is necessary, the involvement of interventional radiology becomes crucial. Upon confirmation of hormonally active adrenal adenoma, the patient would require an adrenalectomy, which should ideally be performed by a surgeon with specialized training in endocrine surgery. Effective communication among healthcare professionals is paramount, as the patient's health status can often undergo frequent changes during the process of diagnosis and management.
Deterrence and Patient Education
Adrenal adenomas cannot be predicted or prevented. It is recommended that patients consult with endocrinology specialists for further evaluation whenever abnormal findings are detected during an imaging study, regardless of whether they are related to the initial issue that prompted the specific testing.
Upon diagnosis, patients should receive thorough education regarding the symptoms associated with Cushing syndrome and primary hyperaldosteronism. These symptoms may include weight gain, fatigue, depression, menstrual irregularities, proximal muscle weakness, acne, purple stretch marks, and hypertension. Patients should promptly notify their healthcare providers if they experience any of these symptoms at any time.
Clear instructions should be provided to patients undergoing hormonal workups, as these tests can be quite cumbersome. Examples of instructions for the low-dose dexamethasone suppression test and the ARR test are provided below.[30][32] Please note that the healthcare provider should customize and adjust these instructions according to each patient's specific situation and needs.
Patient low-dose dexamethasone suppression test instructions:
- Discuss all medications you are currently taking with your healthcare provider before testing. For women, if possible, refrain from taking oral contraceptives or estrogen replacement therapy for at least 6 weeks before the test.
- Take the prescribed dosage of dexamethasone (1 mg) orally between 11 PM and 12 AM as directed by your healthcare provider.
- Have your morning labs collected between 7 AM and 8 AM on an empty stomach the following morning.
Patient ARR test instructions:
- Consult your healthcare provider about all medications you are taking before testing. If any medication needs to be withheld, wait 4 to 6 weeks before proceeding with the test.
- Ensure that your diet includes increased sodium and potassium content in the 4 weeks before testing and avoid consuming licorice products.
- Monitor your blood pressure daily using a home monitor daily, and promptly inform your healthcare provider if your blood pressure readings are elevated.
- Remain in a seated or standing position, on the day of your lab tests for approximately 2 hours before undergoing the tests. If possible, stay seated with your feet on the ground for 5 to 15 minutes immediately before your blood is drawn.
Enhancing Healthcare Team Outcomes
Adrenal adenomas are typically incidental findings, which can generate substantial anxiety for patients and healthcare providers. Therefore, it is crucial to establish a definitive diagnosis and ensure appropriate follow-up. Adopting an interprofessional approach involving primary care providers (such as nurse practitioners, physician assistants, and primary care physicians), endocrinologists, radiologists, and endocrine surgeons, along with nurses and pharmacists, depending on the course of treatment, can help achieve favorable outcomes. Pharmacists are crucial in evaluating medications, checking for potential drug-drug interactions, and educating patients about proper medication use. Nurses with specialty training in endocrinology and surgery help in monitoring patients with adrenal adenomas. They closely observe patients, assess their condition, and promptly inform the interprofessional team of any changes or updates. Even in cases of hormonally inactive adrenal adenomas, it is advisable to maintain long-term follow-up with periodic imaging and hormonal assessments. This approach is essential because these adenomas can later enlarge or become hormonally active.[39]
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