The adrenal glands are small glands that are located just above each kidney (they are sometimes called the suprarenal glands for that reason). The adrenal glands are surrounded by a layer of connective tissue and a layer of fat. They are triangular in shape and consist of several distinct parts:
The central part of the gland is called the adrenal medulla and has a gray-white appearance. It produces the chemicals epinephrine (also called adrenaline) and norepinephrine. Both of these chemicals are involved in regulation of the nervous system. Epinephrine controls the short-term stress response (aka fight-or-flight response). While norepinephrine also plays a role in short-term stress response, it functions in regulating mood and attention, as well.
The outside part of the gland surrounding the medulla is the adrenal cortex, which has a yellow appearance. This part of the adrenal gland is largely responsible for producing steroid hormones in the body. There are several types of steroid hormones that are produced by the adrenal glands. Mineralocorticoids (such as aldosterone) are steroid hormones that help regulate the salt levels in the body by controlling the absorption and excretion of salt and water in the kidneys. This in turn helps to regulate blood pressure. Glucocorticoids (such as cortisol) are steroid hormones that play a critical role in the regulation of 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 produces several sex steroid hormones, including androgens (critical for male sexual development) and precursors to estrogen (critical for female sexual development).
Normally, cells in the body will grow and divide to replace old or damaged cells. This growth is highly regulated, and once enough cells are produced to replace the old ones, normal cells will stop dividing. Tumors occur when there is an error in this process, and cells continue to grow in an uncontrolled manner. Tumors can either be benign or malignant. Although benign tumors can grow in an uncontrolled way, they do not spread to other parts of the body (metastasize), nor do they invade surrounding tissues. Malignant tumors (also known as cancers) will grow uncontrolled in such a way that they invade and damage other tissues around them. They also gain the ability to break off from where they start and spread to other parts of the body, usually through the blood stream or through the lymphatic system where the lymph nodes are located (a process known as metastasis).
The most common tumor of the adrenal gland is actually a benign tumor called an adrenal adenoma. In most patients, these benign tumors never cause a patient to have any symptoms and do not need to be treated. They are usually found when a patient has a CT (or CAT) scan of the body for an unrelated reason, and are thus sometimes called "incidentalomas". 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 blood stream. Several different types of cancer may spread to the adrenal glands, most commonly melanomas, lung cancers, and breast cancers. The adrenal glands are the fourth most common site in the body for cancer cells to metastasize to, after the lungs, liver, and bone.
Cancers can arise directly within the adrenal glands themselves; however, these are relatively rare. Cancers may arise directly from the adrenal cortex, and are called adrenal cortical cancers. 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. 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 elsewhere individually, will not be discussed further in this review.
Other types of adrenal cancers can occur, such as lymphoma; however, these cases are rare.
Both adrenal adenomas and adrenal cortical cancers can produce excess steroid hormones, producing symptoms, which lead to further workup and the identification of the tumor. Symptoms vary depending on the steroid that is produced. If too much aldosterone, which is a type of steroid hormone, is produced, Conn's syndrome (also known as primary hyperaldosteronism) can develop. Conn's syndrome most commonly 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 elevated blood pressure, decreased levels of potassium in the blood, and decreased levels of a chemical produced by the kidneys called renin in the blood. 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 separate steroid hormone produced within the adrenal cortex. If a tumor produces 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 excessive levels of adrenal cortical stimulating hormone (also known as ACTH, a hormone that is responsible for stimulating the adrenal glands to produce cortisol) produced 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 greatly from patient to patient and involve a number of different parts of the body. Symptoms include weight gain and water retention resulting in a round face and 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 (called hirsutism) can also be seen. Excessive cortisol levels can interfere with the body's immune system predisposing a patient to unusual infections. Patients with Cushing's syndrome are at high risk for development of 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).
Adrenal tumors may also cause excess production of sexual hormones. If excess testosterone is produced, virilization can occur in either men or women. Virilization causes increased masculine characteristics, resulting in deepened voice, loss of hair, and 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).
Adrenal tumors may also cause symptoms by occupying space in the abdomen. Patients with large adrenal tumors may experience feelings of abdominal fullness or localized pain. Patients may feel as though they are quickly full when eating and may experience weight loss. In some cases of large adrenal tumors, patients may actually feel a mass in their abdomen.
Each year, there are approximately 500 cases of adrenal cortical cancers in the United States. These most commonly occur in patients between the ages of 30 and 50; however, children under the age of 5 develop adrenal cortical cancers at a higher rate than the rest of the population. Males are more likely to develop non-functioning adrenal carcinomas, while females are more likely to develop functioning adrenal carcinomas. In general, causes of adrenal cortical cancers are unknown. They are not associated with smoking, and do not run in families. Despite this, certain rare genetic syndromes such as Beckwith-Wiedemann syndrome, and multiple endocrine neoplasia, have been associated with adrenal cortical cancers.
Given that the causes of adrenal cortical cancers are unclear, there are no known interventions that can reduce the risk of developing them.
Functioning adrenal cortical cancers and adenomas are frequently diagnosed because of the symptoms caused by steroid hormones. Patients with Cushing's syndrome need to be evaluated to see if the syndrome is caused by 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 performed while giving the patient an extra dose of steroids to see how the body responds. After this is done, most patients undergo 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.
In patients with excess levels of aldosterone, patients should be tested for blood levels of the chemical renin. In cases of hyperaldosteronism due to a tumor in the adrenal gland, renin levels will be low. In patients who have elevated aldosterone levels due to a problem with the blood vessels of the kidney (a condition called renal artery stenosis), renin levels in the blood are high.
In addition to tests for increased steroid production, radiographic imaging is an important part of the diagnosis of adrenal tumors. Computed Tomography (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.
Ultrasound is sometimes used in the diagnosis of adrenal tumors. Ultrasounds use sound waves to form a picture of the inside of the body. At times, it can be difficult to tell if an adrenal tumor is an adenoma or a cancer. For tumors that are larger than 3 cm, ultrasound is a good method of telling the difference between the two.
Another type of imaging that is used when it is unclear if an adrenal tumor is an adenoma or cancer is Magnetic Resonance Imaging (MRI). MRI uses magnets to produce a very sharp picture of the inside of the body. Certain types of changes on MRI are more commonly seen in adrenal cancers than adenomas and can be used to tell the two apart.
Positron Emission Tomography (PET) scans use radioactively labeled sugar to find rapidly growing cells within the body. When cells are dividing quickly, they require a lot of energy, and the main source of energy in the body is sugar. Areas of actively dividing tissue will require more sugar than slowly dividing tissue. Because cancer cells are rapidly dividing and growing, they take up more the radioactively sugar than the surrounding tissue and this can be detected by the PET scanner. PET scans have been very useful in detect a number of different types of cancers. Its use in adrenal cancers is still being studied.
Ultimately, the only way to tell for sure if an adrenal tumor is an adrenal adenoma or cancer, part of the tumor must be examined underneath a microscope. In most cases of suspected cancer, this is done by obtaining a biopsy of the tumor. A small piece of the tumor is taken, usually through a needle, and examined underneath a microscope. In the case of adrenal tumors, this procedure is usually performed while the patient is undergoing a CT scan, so that the radiologist can see where the needle is going in the body. In some cases, this can also be done using an ultrasound to guide the biopsy.
In addition to diagnosing adrenal cortical cancers, the radiographic imaging performed also helps to determine the stage of the patient. According to the seventh edition of the American Joint Committee on Cancer (AJCC), which defines cancer staging systems,, patients with adrenal cortical cancer are divided into one of four stages,. Please note that there is no AJCC staging system for medullary adrenal carcinoma.
Stage I: The cancer is smaller than 5 cm and has not spread outside of the adrenal gland.
Stage II: The cancer is larger than 5 cm and has not spread outside of the adrenal gland.
Stage III: The cancer has spread into the fat surrounding the adrenal gland or has spread to lymph nodes or other organs near the adrenal gland.
Stage IV: The cancer has spread to other parts of the body.
Most adrenal adenomas are detected on a CT scan or MRI scan that is performed for an unrelated reason. It is only necessary to treat them if they are causing symptoms. Otherwise, they can be followed with repeated scans periodically. In the event that an adenoma does need to be treated, surgical removal is the most frequent treatment used. In many cases, this can be performed using a laparoscopic procedure. A laparoscope is a small fiberoptic camera that can be inserted into the abdomen through small incisions. Other small instruments can also be inserted 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 instruments are inserted. Occasionally, because of the size or location of the adenoma, a laparoscopic procedure cannot be performed, and a large incision will need to be made in the abdomen in order to remove the tumor.
In the majority of cases of hyperaldosteronism, symptoms resolve with surgical removal of the adenoma; however, 30% of patients will have repeat episodes of high blood pressure even after the adenoma is removed. If the adrenal adenoma produces cortisol, the patient should take steroids by mouth before and for some time after the surgery until the body is able to produce these steroids on its own again.
Currently, the only known way to cure adrenal cortical cancers is complete surgical removal of the tumor. Unfortunately, this is only possible for some patients with this disease. At least half of patients with adrenal cortical cancers have metastases or cancer invading into other organs, so that complete removal of the tumor is not possible. The best results with surgical resection have been with an en bloc resection, meaning that the entire tumor is removed in one piece. This also includes removing the entire kidney on the same side as the adrenal cancer. Because of this, it is unusual for adrenal cancers to be removed using a laparoscopic procedure, although as techniques of laparoscopic resection improve, more patients are being treated with this method. Occasionally, 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 performed, but will require input from a general surgeon, an urologist, and a vascular surgeon.
Even in cases where the tumor cannot be removed in its entirety, surgical removal of as much tumor as possible can improve symptoms, particularly if they are due to excessive steroid secretion.
Chemotherapy refers to a group of medications that are given intravenously or orally as a pill. These drugs travel throughout the body to kill cancer cells. This is one of the big advantages of chemotherapy. If cancer cells have broken off from the tumor and are somewhere else inside the body, chemotherapy has the chance of killing them. A number of different chemotherapeutic agents exist, each with its own side effects. You should discuss the potential side effects of any chemotherapy you may receive with your medical oncologist.
The most common chemotherapy used in treatment of adrenal cortical cancers is mitotane. Mitotane acts to block the hormones produced 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 tumor remains in the body. In many cases, Mitotane is also used for patients after surgery even if every visible cancer cell has been removed. Streptozosin is a second chemotherapy drug that has been shown to work in combination with mitotane. Mitotane with or without streptozosin has been shown in clinical trial to reduce the risk of adrenal cortical cancers growing back after they are removed surgically. Even if cancers cannot be removed surgically because they have spread to other parts of the body, mitotane may cause tumors to shrink and reduce symptoms.
Exactly which chemotherapeutic agents are given varies according to the physician giving them. Based on your own health status and the risks of side effects that you are willing to accept, the choice of chemotherapy can vary.
Radiation therapy is used in a number of cancers as both the main method of killing cancer cells or in combination with surgery (either before or after). The radiation comes in the form of high-energy x-rays that are delivered to the patient only in the areas at highest risk for cancer. These x-rays are similar to those used for diagnostic x-rays, only of a much higher energy. The high-energy of x-rays in radiation therapy results in damage to the DNA of cells, causing tumor cells to die.
Radiation therapy is not part of the routine management of adrenal cancers, particularly in cases where the cancer is completely removed by surgery. Radiation has been tried in cases where surgical removal of the cancer is incomplete or in cases where the cancer comes back after surgery. In these cases, the radiation is usually delivered daily, Monday through Friday, 5 days a week, for a total of 5 to 7 weeks. In general, the side effects associated with this treatment include fatigue, skin redness and irritation, nausea, and diarrhea.
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. Physicians may recommend other medications, such as ketoconazole or metyrapone, to treat these symptoms.
In general, adrenal cortical cancers are curable only in cases where the entire tumor is removed at surgery. Unfortunately, these tend to be aggressive cancers. Even when complete surgical removal is performed, they have a tendency to come back. The likelihood of this happening after a complete surgical resection is dependent upon the stage of the tumor. The 5-year overall survival describes the percentage of patients who are alive at 5 years after cancer treatment. After total tumor removal for stage I and II adrenal cortical cancers, the 5-year overall survival rate is 40-60%. For stage III cancers, the 5-year overall survival is 20%. For stage IV patients, the 5-year overall survival is 10%. There is a small percentage of patients who have slow-growing adrenal cortical cancers that can take a number of years to progress. It is unclear why these adrenal cancers act differently than the majority of adrenal cancers; however, these cases explain why 10% of patients who have disease that has spread to other parts of the body at the time of diagnosis (stage IV) are still alive at 5 years after diagnosis, despite the generally aggressive nature of these cancers.
In most cases, when other cancers spread to the adrenal glands, they are treated with chemotherapy that is known to be effective against the original cancer type. In some cases, if the adrenal gland is the only site in the body where the cancer appears to have spread, surgical resection of metastatic cancer and the adrenal gland can be performed, followed by treatment to the primary site where the cancer started. This has been shown to be curative in a small number of patients, particularly in the case of lung cancer.
Shortly after treatment for functional (secreting) adrenal tumors, blood will be drawn to measure hormone levels in the body. If the hormone levels have returned to normal after therapy, regular follow-up will occur. You will be followed every 3-6 months for several years after treatment. In the case of non-functional (non-secreting) adenomas and adrenal cortical cancers, periodic follow-up MRI or CT of the abdomen will be obtained for the first few years.
Adrenal Cortical Cancer Overview from the ACS
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