Adrenal Adenoma

What is Adrenal Adenoma?

Adrenal adenomas are non-cancerous growths that originate from the adrenal cortex, a part of the adrenal glands. These growths are often found accidentally during abdomen scans, thus they are sometimes referred to as “adrenal incidentaloma.” The significance of adrenal adenomas is that they can potentially produce adrenal hormones.

The adrenal glands, located above the kidneys, produce hormones and are made up of medullary and cortical tissues. The adrenal medulla, which makes up about 15% of the adrenal mass, reacts to stress by producing and releasing certain hormones as part of your body’s stress response. Meanwhile, the adrenal cortex has distinct regions each responsible for producing specific hormones.

When an unexpected mass within the adrenal gland is detected, either incidentally or due to symptoms, it is key to distinguish between benign (non-cancerous) and malignant (cancerous) masses, as well as hormone-producing and non-hormone-producing masses. This evaluation is critical not only for accurate identification but also for ruling out potentially life-threatening cancers.

Adrenocortical carcinoma and pheochromocytoma are examples of potentially cancerous growths that can occur in the adrenal glands. Unlike adenomas, these tumors can grow beyond the adrenal gland, potentially leading to the spread of cancer to other parts of the body (metastasis).

On the other hand, adrenal adenomas are not likely to turn into cancer. If these adenomas are small and do not produce hormones, no further treatment may be needed. However, when an adenoma overproduces adrenal hormones, such as cortisol or aldosterone, the treatment approach involves managing this hormonal imbalance and considering surgical removal.

Adenomas that produce excessive cortisol can manifest different symptoms depending on how much hormone is produced. If a large amount of cortisol is produced leading to systemic symptoms, this is typically an indication of Cushing syndrome. Whereas, adenomas that produce cortisol in lower quantities, without clear signs of hypercortisolism (excessive cortisol), are known as mild autonomous cortisol secretion (MACS) tumors.

What Causes Adrenal Adenoma?

Our understanding of the genetics behind adrenal adenomas, or benign tumors in the adrenal gland, is changing quickly. Specific genetic changes have been tied to these tumors, both those that are hormonally active and non-active. However, scientists aren’t exactly sure how these changes lead to the formation of these tumors.

Changes in a gene called CTNNB1, which makes a protein known as beta-catenin, have been tied to the development of larger adrenal adenomas that don’t secrete hormones.

Certain genes, such as PRKACA, GNAS1, MENIN, ARMC5, APC, and FH, have been associated with large cortisol-producing adrenal nodules. These nodules are often associated with conditions like cortisol-producing adenoma, McCune-Albright syndrome, multiple endocrine neoplasm type 1, and primary bilateral macronodular adrenal hyperplasia.

Smaller cortisol-producing adrenal nodules, also known as micronodular adrenal hyperplasias, result from mutations in other genes such as PRKAR1A, PDE11A, and PDE8B. These genes have been linked to conditions like primary pigmented nodular adrenocortical disease and isolated micronodular adrenocortical disease.

Mutations in genes like KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 have been tied to aldosterone-producing adrenal adenomas. These types of adenomas are adrenal tumors that overproduce the hormone aldosterone. The KCNJ5 gene mutation accounts for around 40% of these cases.

Risk Factors and Frequency for Adrenal Adenoma

Since CT scans are being used more often, adrenal adenomas, or benign tumors of the adrenal glands, are being found more frequently. These innocuous little lumps can be spotted anywhere from 0.35% to 1.9% of the time on CT scans, though autopsies have suggested they show up around 2.3% of the time. They make up for about 54% to 75% of adrenal incidentalomas, which are adrenal tumors discovered by chance during imaging tests for other issues.

Although women seem to have a higher chance of having adrenal adenomas, some studies, like a large one conducted in Korea, found them to be more common in men. The average age at which they’re discovered is 57, but they’ve been found in people as young as 16 and as old as 83.

• 15% of these accidental findings turn out to be ‘overactive’, releasing too many hormones into the body.
• Hypercortisolism, or the overproduction of cortisol, is seen in 1% to 29% of these cases.
• Hyperaldosteronism, where too much aldosterone is produced, is found in 1.5% to 3.3% of incidentalomas.
• In 1.5% to 11% of these accidental tumour findings, a pheochromocytoma, which excessively secretes adrenaline, is detected.

In rare occurrences, there might be not just one, but two nodules, one on each adrenal gland. If you’re this person, doctors would also consider possible causes like cancer spread, a genetic disorder called congenital adrenal hyperplasia, lymphoma, infections, bleeding or other adrenal gland disorders.

Signs and Symptoms of Adrenal Adenoma

Adrenal adenomas are usually found by accident during abdominal imaging because they don’t cause symptoms when they don’t produce a lot of hormones. However, if these adenomas produce too many glucocorticoids, they may cause Cushing syndrome. For tumors that produce aldosterone, common symptoms include resistant high blood pressure and low potassium levels. Additional issues might include muscle weakness, low magnesium levels, and high sodium levels. The way symptoms present can vary in men and women when the adenoma produces aldosterone. For example, adult men may notice a reduction in testes size, while adult women might experience changes in their menstrual cycle, excessive hair growth, baldness, and acne due to elevated androgen levels.

• Adrenal adenomas usually don’t cause symptoms
• If an adenoma produces excess glucocorticoids, it may lead to Cushing syndrome
• Resistant high blood pressure and low potassium levels are common symptoms for aldosterone-producing tumors
• Additional symptoms might include muscle weakness, low magnesium levels, and high sodium levels
• Men with these adenomas might observe a reduction in testes size
• Women may experience menstrual irregularities, excessive hair growth, male-pattern baldness, and acne due to high androgen levels

Testing for Adrenal Adenoma

When examining adrenal tumors, doctors aim to find out two main things: whether the tumors are benign or malignant, and if they produce hormones or not. To investigate these tumors, CT scans or MRI (Magnetic Resonance Imaging) are commonly used. Adrenal tumors that are larger than 4 centimeters are very likely to be cancerous. Also, benign tumors (adenomas) generally show up as less than 10 Hounsfield units (a measurement unit in CT scans).

Sometimes, benign adenomas may appear with higher than 10 HU values. In this case, doctors can use a contrast-enhanced CT scan to better differentiate between benign and malignant tumors. This method, however, has been recently found less reliable in distinguishing benign adenomas. MRI could be utilized as an alternative technique.

Before hormonal testing for adrenal adenomas, it’s important to rule out a condition called pheochromocytoma, which is often hard to diagnose based only on imaging. After ensuring the tumor is not malignant and not a pheochromocytoma, it’s vital to check if the patient is producing excessive cortisol which can present symptoms like either Cushing syndrome or MACS.

The favourite first test for Cushing syndrome and MACS is the low-dose dexamethasone suppression test. This involves taking a small dose of dexamethasone (a medicine) at night and having a blood test the following morning to measure cortisol levels. If the morning blood cortisol level is under 1.8 mcg/dL after taking dexamethasone, it’s unlikely the patient has excess cortisol.

Patients with an adrenal adenoma and high blood pressure should be tested for primary hyperaldosteronism, a condition of excessive aldosterone hormone. The go-to test for this condition is the aldosterone-plasma renin ratio (ARR). The preparation for ARR testing can be complicated and involves adjustments to medication and diet.

Fine-needle aspiration (FNA) biopsy of adrenal tumors is generally not needed unless the imaging data is unclear and more information is required for treatment. However, any invasive procedure, including a biopsy, should not be done without ruling out a pheochromocytoma first, as this could lead to serious complications like sudden high blood pressure, rapid heart rate, and tremors.

Treatment Options for Adrenal Adenoma

Removing one adrenal gland is the preferred way to treat large adenomas (benign tumors) over 4 cm, those believed to be malignant, or those that are producing hormones. This latter group of tumors may show signs of Cushing syndrome or primary hyperaldosteronism. While removing the adrenal gland hasn’t been proven to be better than medication for managing Mild Autonomous Cortisol Secretion (MACS), adrenal experts have suggested surgery may be an option for younger patients with MACS who have worsening diabetes, high blood pressure, or osteoporosis. It’s crucial that patients discuss these options with their healthcare providers for the best decision.

Managing hormone-secreting adenomas with medication is usually reserved for patients who aren’t good candidates for surgery because of their age, serious health conditions, or personal choice. In such instances, the goal is to relieve symptoms and block hormone receptors. For patients secreting excessive cortisol, mifepristone, a drug that blocks cortisol receptors, can be used. Ketoconazole can be another option because of its direct effects on the adrenal glands. Patients with over-secretion of the hormone aldosterone should be treated with drugs that block its receptors, like spironolactone or eplerenone.

Adenomas that aren’t producing hormones are typically managed by repeating imaging tests every 3 to 6 months, followed by annual imaging for 1 to 2 years. Hormonal assessments should be done yearly for 5 years. If the adrenal gland’s size increases by more than 1 cm or starts secreting hormones, removing the gland is recommended.

What else can Adrenal Adenoma be?

The possible conditions that could be confused with the main diagnosis are:

• Cancerous tumors (Carcinoma)
• Cancer that has spread from the original location to other parts of the body (Metastasis)
• Enlargement of an organ due to an increase in the size of its cells (Nodular hyperplasia)
• Fluid-filled sacs that can occur anywhere in the body (Cysts)
• A rare, noncancerous tumor often found in the adrenal gland (Myelolipoma)
• A noncancerous tumor typically found in the kidneys (Angiomyolipoma)
• A noncancerous birthmark that often appears at birth or in the first or second week of life (Hemangioma)
• A rare tumor of the adrenal gland that can release high levels of adrenaline (Pheochromocytoma)
• A noncancerous tumor (Hamartoma)
• An uncommon condition where the immune system attacks the body’s own cells and organs (Granulomatosis)

These potential diagnoses should be thoroughly investigated and ruled out before confirming the main diagnosis.

What to expect with Adrenal Adenoma

The long-term outlook for patients with adrenal adenomas is usually very good. Often, these nonfunctioning adrenal adenomas don’t even need treatment. There are instances though where adrenal tumors, which don’t initially produce too much of any hormone, can start producing excessive hormones. It was estimated that 17%, 29%, and 47% of these tumors could start producing excess hormones over the span of 1, 2, or 5 years, respectively. However, it’s important to note that it’s very rare for an adrenal adenoma to transform into adrenocortical carcinoma, a type of cancer.

Possible Complications When Diagnosed with Adrenal Adenoma

Cushing syndrome, often caused by a tumor in the adrenal gland that produces high levels of cortisol, is linked to numerous health problems. Notably, it leads to metabolic and cardiovascular issues. This is mainly because the excess cortisol in the body makes it resistant to insulin, causing an increase in belly fat. This condition has been observed in other types of adrenal gland tumors as well.

Furthermore, this overproduction of cortisol affects the body’s hormone regulation, reducing levels of T3/T4 hormones. It also decreases the production of growth hormones.

The main problem with tumors that cause high aldosterone levels is uncontrolled high blood pressure. If not diagnosed and treated properly, it can cause the body to retain too much sodium and water, leading to problems like fluid overload, heart failure, irregular heartbeat, and heart attack.

In rare cases, adrenal tumors that do not produce hormones can still cause problems due to their size. However, it’s crucial to remember that large lesions are usually cancerous.

Possible complications:

• Metabolic issues
• Cardiovascular disorders
• Increase in belly fat
• Decreased levels of T3/T4 hormones
• Reduced growth hormone production
• Uncontrolled high blood pressure
• Fluid overload
• Heart failure
• Irregular heartbeat (atrial fibrillation)
• Heart attack (myocardial infarction)
• Physical problems caused by large, usually cancerous, nonfunctioning adrenal tumors

Recovery from Adrenal Adenoma

The decision to have surgery is made after in-depth discussions between the patient and their healthcare provider, weighing the potential complications of the disease and the risks involved with surgery. If detailed tests confirm that the adenoma (a type of tumor) isn’t producing hormones, surgery isn’t necessary. However, if the adenoma is only on one side and is producing hormones, the best treatment option is removal of the adrenal gland, known as an adrenalectomy.

Patients with Cushing syndrome and MACS produce too much cortisol, which over time suppresses the body’s stress-response system, called the hypophyseal-pituitary-adrenal (HPA) axis. After surgery, these patients require a supplement of the hormone glucocorticoid during their recovery, which could take several months. According to the Endocrine Society, it’s recommended to start this supplementation the day after surgery, and to divide the daily dosage into 2 or 3 doses throughout the day. Recent studies show that taking glucocorticoid 3 times a day helps control cortisol levels. If patients can’t tolerate multiple doses a day, prednisolone can be used as an alternative, but even with this replacement, some patients may still have symptoms of adrenal insufficiency, which is the body’s inability to produce enough hormones.

If patients experience symptoms like fatigue, weight loss, muscle pain, weakness, stomach pain, low blood pressure when standing up, or new depression-like symptoms, they should inform their doctors. Additionally, patients should be educated on how to adjust their glucocorticoid dosage when sick. In general, if a patient gets a minor illness, they should double their daily dose of glucocorticoid. After surgery, it is recommended to reassess the patient’s HPA axis every 3 to 6 months by measuring cortisol levels and performing an ACTH (a hormone) stimulation test.

Patients who undergo an adrenalectomy for hyperaldosteronism (an overproduction of the hormone aldosterone) should also have their aldosterone and renin (another hormone) levels tested the same day as the surgery to monitor their response. However, renin levels may not increase immediately after the procedure, so it’s necessary to monitor other factors, like aldosterone levels and blood pressure, at the same time.

After surgery, it might be possible to stop potassium replacement and the use of the medication spironolactone. However, if the patient still suffers from high blood pressure after the operation, medication to manage it should be continued. It should be noted that it may take some time for blood pressure to improve, possibly even up to a year, after surgery.

Preventing Adrenal Adenoma

There’s no known way to foresee or prevent adrenal adenomas, or tumors of the adrenal glands. It’s crucial for patients to talk to a specialist in hormones (endocrinologist) if an imaging scan reveals anything abnormal, even if it isn’t related to the original health concern.

Upon being diagnosed, patients should be taught about the possible symptoms of both Cushing syndrome and primary hyperaldosteronism, which are conditions related to overactive adrenal glands. Symptoms can range from weight gain, tiredness, and depression, to changes in menstrual cycles, muscle weakness, acne, purple stretch marks, and high blood pressure. It’s important to inform your doctor promptly if any of these symptoms appear.

Patients going for hormone tests should receive clear instructions because these tests can be complex. Here are examples of instructions for two such tests, the low-dose dexamethasone suppression test and the ARR test. Remember, these are just examples – your doctor will tailor the instructions to your specific situation and needs.

Instructions for the low-dose dexamethasone suppression test:

1. Before the test, discuss all medications you’re taking with your doctor. Women should, if possible, avoid taking the pill or estrogen therapy for six weeks before the test.
2. Take your prescribed dose of dexamethasone (1 mg) by mouth between 11 PM and midnight, as your doctor instructs.
3. The next morning, fast and then have your blood taken between 7 AM and 8 AM.

Instructions for the ARR test:

1. Talk to your doctor about all the medications you’re taking before the test. If you have to stop any medication, wait 4 to 6 weeks before you have the test.
2. Make sure your diet has plenty of sodium and potassium for the 4 weeks before the test, and don’t eat any licorice products.
3. Check your blood pressure every day at home and let your doctor know right away if it’s high.
4. On the day of the tests, stay seated or standing for about 2 hours before the tests. If you can, sit with your feet on the floor for 5 to 15 minutes just before your blood is taken.