All About Adrenal Cancer

What are the adrenal glands?

The adrenal glands produce hormones. Hormones are chemicals made by the body. The blood carries these hormones to organs and tissues in the body where they are used. The adrenal glands make hormones such as adrenaline, aldosterone, and cortisol. 

You have two adrenal glands, each located just above each kidney. The adrenal glands are covered by a layer of connective tissue and a layer of fat. Each adrenal gland has two parts: the outer portion, which is the adrenal cortex, and the inner portion, which is the medulla.

• The medulla (the inner portion) makes the chemicals epinephrine (also called adrenaline) and norepinephrine. Both of these chemicals help regulate the nervous system. 
  • Epinephrine controls the short-term stress response (fight-or-flight response). 
  • Norepinephrine plays a role in short-term stress response and helps regulate mood and attention.
• The adrenal cortex (the outer portion) makes steroid hormones. There are many types of steroid hormones made by the adrenal glands. 
  • Mineralocorticoids (such as aldosterone) are steroid hormones that help regulate the sodium (salt) levels in the body. They do this by controlling the absorption (intake) and excretion (output) of salt and water in the kidneys. This helps regulate blood pressure. 
  • Glucocorticoids (such as cortisol) are steroid hormones that help regulate sugar within the body. These hormones also help to regulate the fat stores within the body, act as a strong anti-inflammatory force, and play an important role in fetal development, particularly in lung maturation. 
  • The adrenal cortex also makes several sex steroid hormones, including androgens (critical for male sexual development) and precursors to estrogen (critical for female sexual development).

What is adrenal cancer?

Cells in the body grow and divide to replace old or damaged cells. This growth is highly regulated, and once enough cells are made to replace the old ones, normal cells stop dividing. Tumors occur when there is an error in this regulation and cells continue to grow in an uncontrolled way. Tumors can either be benign or malignant. Benign tumors do not spread beyond the part of the body where they started (metastasize) and do not grow into nearby tissues. Malignant tumors can invade and damage other tissues around them. They also may spread to other parts of the body, usually through the bloodstream or through the lymphatic system where the lymph nodes are found.

Over time, the cells in a malignant tumor become more abnormal and look less like normal cells. This change in the appearance of cancer cells is called the tumor grade, and cancer cells are described as being well-differentiated, moderately-differentiated, poorly-differentiated, or undifferentiated. Well-differentiated cells are quite normal appearing and look like the normal cells from which they started. Undifferentiated cells are cells that have become so abnormal that often we cannot tell what types of cells they started from.

The most common tumor of the adrenal gland is a benign tumor called an adrenal adenoma. In most patients, these benign tumors never cause any symptoms and do not need to be treated. They are usually found when a patient has a CT scan of the body for an unrelated reason, and are called "incidentalomas" because they are found accidentally. An adrenal adenoma will cause symptoms if it is making an excess of hormones like aldosterone, which can cause high blood pressure.

Cancers that arise directly from the adrenal cortex are called adrenal cortical carcinoma (also called adrenocortical cancer or adrenal cancer). Like an adenoma, they are often found through imaging such as a CT for an unrelated issue. However, they can be found after a workup for symptoms that they are causing. Symptoms of overproduction of hormones include: weight gain, fluid retention, early puberty in children, or excess facial hair growth in women. A large adrenal tumor can cause symptoms such as pain or a feeling of fullness since the tumor may press against other organs due to its size. These cancers can either be functioning (meaning they secrete excess steroid hormones) or non-functioning (meaning they do not secrete steroids). Functioning adrenal cortical cancers are more common than non-functioning cancers.

The most common malignant tumors found in the adrenal gland are tumors that come from cancer cells that have metastasized (or spread) from other parts of the body to the adrenal gland through the bloodstream. Several different types of cancer may spread to the adrenal glands, most commonly melanomas, lung cancers, and breast cancers.

Cancers can also arise within the adrenal medulla, the most common of which are pheochromocytomas. In children, neuroblastoma tumors can develop within the adrenal medulla. Pheochromocytomas and neuroblastomas are discussed in separate articles and will not be discussed further in this review. Other types of adrenal cancers can occur, such as lymphoma; however, these cases are rare.

What causes adrenal cancer and am I at risk?

Adrenal cancer is very rare and the actual number of those diagnosed in the United States is not known. It is estimated to be about 200 new cases diagnosed each year. About one in every 10 people who have an imaging test of the adrenal glands are found to have adrenal tumors but many of these are adenomas (benign tumors). Adenomas are fairly common in the middle-aged and elderly population. Adrenal cancer is more common in women than men.

There are risk factors for adrenal cancer. Having one or more of these risk factors does not mean you will get adrenal cancer. You could have no risk factors and develop adrenal cancer. A number of genetic-related syndromes are linked to adrenal cancer, including: Li Fraumeni syndrome, Beckwith-Wiedmann syndrome, multiple endocrine neoplasia, hereditary nonpolyposis colorectal cancer, and familial adenomatous polyposis. These syndromes are caused by genes you inherit. These are things you cannot change. High-fat diet, smoking, sedentary lifestyle, and exposure to cancer-causing substances can all increase your risk for cancer in general, but not specifically adrenal cancer.

How can I prevent adrenal cancer?

There is no specific way to prevent adrenal cancer. Your provider may suggest genetic testing and counseling if you have a family member with any of the previously mentioned syndromes.

What screening tests are used for adrenal cancer?

Adrenal cancers are rare and there are no recommendations for routine screening.

What are the signs of adrenal cancer?

Both adrenal adenomas and adrenal cancers can make excess steroid hormones which lead to symptoms. This leads to further workup. Symptoms depend on the steroid that is being made.

• Aldosterone, a type of steroid hormone, can cause Conn's syndrome (primary hyperaldosteronism). Conn's syndrome most often occurs with pituitary adenomas, but it can also occur in the setting of adrenal hyperplasia (an overgrowth of normal adrenal cortical tissue) and adrenal cortical cancers. Signs of Conn's syndrome include high blood pressure, low potassium levels, and low levels of renin. Renin is a chemical made by the kidneys. In most cases of Conn's syndrome, elevations in blood pressure are mild to moderate. Other symptoms include weakness, muscle cramps, increased thirst, and increased frequency of urination.
• Cortisol is a steroid hormone made within the adrenal cortex. If a tumor makes excess cortisol, Cushing's syndrome (also known as hypercortisolism) can develop. This syndrome is seen not only with adrenal tumors, but can also be the result of too much adrenal cortical stimulating hormone (also known as ACTH, a hormone that is responsible for stimulating the adrenal glands to produce cortisol) made by the pituitary gland or another tumor in the body. Cushing's syndrome may also develop in patients who are taking steroids as medication for other disorders. The symptoms of Cushing's syndrome can vary and involve a number of different parts of the body. Symptoms include weight gain and water retention that result in a round face and a collection of fat on the back of the shoulders and neck (so-called "buffalo hump"). Red or purple stretch marks, known as striae, can appear on the skin. Excessive hair growth (hirsutism) can also be seen. Excessive cortisol levels can affect the immune system leading to infections. Patients with Cushing's syndrome are at high risk for diabetes. Patients may also have mental changes, including mood swings, irritability, and in the worst case, psychotic episodes. In children, excessive cortisol can lead to premature sexual development and maturation (also called precocious puberty).
• Sexual hormones can also be made by an adrenal tumor. If excess testosterone is made, virilization can occur in either men or women. Virilization causes increased masculine characteristics such as deepened voice, loss of hair, and an increase in the size of the clitoris in women. Feminization may occur in men with excess estrogen production and may cause sexual impotence and/ or breast growth (gynecomastia).

As an adrenal tumor grows it can affect other organs by putting pressure on them causing symptoms. Patients with large adrenal tumors may have feelings of abdominal fullness or localized pain. Patients may feel as though they are quickly full when eating and may have weight loss. In some cases of large adrenal tumors, patients may feel a mass in their abdomen.

How is adrenal cancer diagnosed?

Functioning adrenal cortical cancers and adenomas are often diagnosed because of the symptoms from the overproduction of hormones caused by the cancer. A full workup will be done to find the cause of this overproduction and if it is related to an adrenal tumor.

Patients with Cushing's syndrome could have a problem in the adrenal glands, the pituitary gland, or another tumor somewhere else in the body. The first step is measuring the amount of cortisol in the urine (called a 24-hour urinary-free cortisol test). This test is sometimes done while giving the patient an extra dose of steroids to see how the body responds. After this is done, most patients have a dexamethasone suppression test where patients are given a high dose of the steroid dexamethasone. In normal patients, and in patients with Cushing's syndrome due to a problem in the pituitary gland, a high dose of dexamethasone will cause the levels of cortisol in the blood and urine to decrease. In patients with adrenal tumors or another tumor in the body that produces ACTH, cortisol levels remain high even after a patient receives a high dose of dexamethasone.

Patients with excess levels of aldosterone should have the blood levels of the chemical renin tested. In cases of hyperaldosteronism due to a tumor in the adrenal gland, renin levels will be low. Patients who have elevated aldosterone levels due to a problem with the blood vessels of the kidney (a condition called renal artery stenosis), will have high blood levels of renin.

Imaging is another important part of the diagnosis of adrenal tumors. Computed Tomography (also referred to as CT or CAT) scans are commonly used. CT scans use x-rays to form a three-dimensional picture of the inside of the body. If the adrenal tumor is larger than 6 centimeters (cm) on CT scan, it is much more likely to be an adrenal cancer than an adrenal adenoma. In most cases, CT scans can also differentiate between a normal adrenal gland and adrenal hyperplasia (enlarged adrenal gland).

Ultrasound and MRI are used less but still can help in diagnosing adrenal cancer. Ultrasounds use sound waves to form a picture of the inside of the body. At times, it can be hard to tell if an adrenal tumor is an adenoma or cancer. For tumors that are larger than 3 cm, ultrasound is a good method of telling the difference between the two. MRI (Magnetic Resonance Imaging) can be useful to see if a growth is cancer. MRI uses magnets to make a very clear picture of the inside of the body. Certain types of changes on MRI are more often seen in adrenal cancers than adenomas and can be used to tell the two apart.

Many cancers are diagnosed using biopsy. A biopsy is a procedure that removes part of or the whole tumor and looks at it under a microscope. This is not the case with adrenal cancer. Adrenal adenomas and cancers look alike under a microscope. It has also been found that the biopsy procedure to diagnose adrenal cancer is likely to spread tumor cells and may cause metastasis of the cancer. Therefore, it is best to use imaging tests and workup of hormonal issues rather than biopsy to diagnose adrenal cancer.

How is adrenal cancer staged?

Tests also help to determine the stage of the tumor. The staging system used to describe adrenal cancer is the "TNM system,” as described by the American Joint Committee on Cancer. The TNM systems are used to describe many types of cancers. They have three parts:

• T-describes the size/location/extent of the "primary" tumor in the lung.
• N-describes if the cancer has spread to the lymph nodes.
• M-describes if the cancer has spread to other organs (metastases). 

The staging system is very complex, and the entire staging system is outlined at the end of this article. Though complicated, the staging system helps healthcare providers determine the extent of the cancer, and in turn, make treatment decisions for a patient's cancer. The stage of cancer, or extent of disease, is based on information gathered through the various tests done as the diagnosis and workup of the cancer is being performed.

How is adrenal adenoma treated?

Adrenal adenomas should be treated only if they are causing symptoms. Otherwise, they can be followed with scheduled scans. If an adenoma needs to be treated, surgical removal is often used. In many cases, this can done with a laparoscopic procedure. A laparoscope is a small fiberoptic camera that can be placed into the abdomen through small incisions. Other small tools can also be placed through these incisions. The adrenal adenoma can be resected while inside the body, without making a large incision in the abdomen, and removed through the small holes through which the camera and other tools are placed. In some cases, because of the size or location of the adenoma, a laparoscopic procedure cannot be done and a larger incision will need to be made.

In most cases of hyperaldosteronism, symptoms go away when the adenoma is removed. Some patients will have repeat episodes of high blood pressure even after the adenoma is removed. If the adrenal adenoma makes cortisol, the patient should take steroids by mouth before and for some time after the surgery until the body is able to make these steroids on its own again.

How is adrenal cancer treated?

Adrenal cancer can be treated in a number of ways. Your provider will talk to you about your options for treatment. 

Surgery

The only way to cure adrenal cortical cancers is to remove the whole tumor. This surgery is called an adrenalectomy. This is possible for some patients with this disease. For patients with metastases or cancer growing into other organs, complete removal of the tumor is not possible. The best results are with an en-bloc resection, meaning that the entire tumor is taken out in one piece. This also may include taking out the entire kidney on the same side as the adrenal cancer. It is unusual for adrenal cancers to be removed using a laparoscopic procedure. However, as techniques of laparoscopic resection improve, more patients are being treated with this method. Sometimes adrenal cancers will grow into the large blood vessel that carries blood back from the lower body to the heart (the vena cava). Even in these cases, complete removal of the cancer can sometimes be done but input from a general surgeon, a urologist, and a vascular surgeon is needed.

Even in cases where the whole tumor cannot be removed, surgical removal of as much tumor as possible can improve symptoms, particularly if they are due to excessive steroid secretion. Some providers may decide that a patient should be treated with chemotherapy or radiation prior to or after treatment with surgery. This depends on the size of the tumor, if there is metastasis, and how successful the surgery was in removing all of the cancer.

Chemotherapy

Chemotherapy is a group of medications that are given to treat cancer. These medications travel throughout the body to kill cancer cells. If cancer cells have broken off from the tumor and are somewhere else inside the body, chemotherapy has the chance of killing them.

The most common chemotherapy used in treatment of adrenal cortical cancers is mitotane. Mitotane acts to block the hormones made by the cancer and can also kill adrenal cancer cells. Mitotane or other chemotherapy is almost always used when surgery is not possible, or if surgery is done, but some cancer cells remain in the body. In many cases, mitotane is also used for patients after surgery, even if all visible cancer has been removed. The two most common chemotherapy regimens are mitotane, etoposide, doxorubicin, and cisplatin or mitotane and streptozocin. Mitotane can also suppress the function of your normal adrenal gland, so you may need to take hormone replacements to prevent adrenal insufficiency. Your lab work will be monitored to see if and which hormones are being affected and what supplements you will need to take.

Your provider will talk to you about which chemotherapy is best for your case.

Radiation Therapy

Radiation therapy is the use of high-energy x rays to kill cancer cells. It is not part often used to treat adrenal cancers. Radiation may be used in cases where surgical removal of the cancer is incomplete or in cases where the cancer comes back after surgery. It may also be used as a palliative treatment. Palliative treatment manages symptoms like pain but does not cure the cancer.  

Other Medication Treatments

Patients who are treated for adrenal cortical cancers may have symptoms that are due to levels of hormones that are either too high or too low. Providers may recommend other medications, such as ketoconazole or metyrapone, to treat these symptoms. Other medications that can be used to block the effects of overproduction of hormones include spironolactone, mifepristone, tamoxifen, toremifene, and fulvestrant.

Clinical Trials

There are clinical research trials for most types of cancer, and every stage of the disease. Clinical trials are designed to determine the value of specific treatments. Trials are often designed to treat a certain stage of cancer, either as the first form of treatment offered or as an option for treatment after other treatments have failed to work. They can be used to evaluate medications or treatments to prevent cancer, detect it earlier, or help manage side effects. Clinical trials are extremely important in furthering our knowledge of disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your provider about participating in clinical trials in your area. You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service.

Follow-Up Care and Survivorship

You will be followed closely for recurrence of the disease and to monitor any side effects of the treatment you received. Your provider will talk to you about what testing you need depending upon your treatment and any new symptoms you may be having. If part of your treatment plan includes taking mitotane, you will have blood drawn to check the level of mitotane in your blood. You may have CT scans to monitor you for recurrence or to check if a tumor is growing. If you are taking medications to suppress hormone production by the cancer, you will have tests of your blood and urine to check hormone levels.

Fear of recurrence, financial impact of cancer treatment, employment issues, and coping strategies are common emotional and practical issues experienced by adrenal cancer survivors. Your healthcare team can identify resources for support and management of these practical and emotional challenges faced during and after cancer.

Cancer survivorship is a relatively new focus of oncology care. With nearly 17 million cancer survivors in the US alone, there is a need to help patients transition from active treatment to survivorship. What happens next, how do you get back to normal, what should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after cancer and helping you communicate knowledgeably with your healthcare providers. Create a survivorship care plan today on OncoLink.

Resources for More Information

Adrenal Cancer Support
This website offers information and support for those affected by adrenal cancer.

http://www.adrenocorticalcarcinoma.org

Appendix: Complete Adrenal Cancer Staging

AJCC, Cancer Staging Manual, 8th Edition