Adrenocortical Carcinoma

Adrenocortical Tumors and Cancer

Adrenocortical carcinoma, cancer of the adrenal cortex, is a rare and dangerous condition affecting 1-2 people per million every year. The mean age at diagnosis is 45, and women are more commonly affected than men.

The adrenal glands are an important part of the endocrine system of the human body. These glands function by producing hormones that are very important for various body functions. They are located right above the kidneys, which although they are close by, have a very different function. The kidneys are part of the genitourinary system meaning they function to filter out some of the body's waste and transport it to the bladder to be disposed (urine). The adrenal cortex (outer part of the gland) secretes cortisol, aldosterone, and androgens, which are essential for affecting blood pressure, salt concentrations in the body, and sex characteristics, respectively, as well as kidney function. The medulla (inner part of the gland) secretes epinephrine (adrenaline) and nonepinephrine (noradrenaline), which are triggered by physical and mental stress.

Rarely can an adrenal gland become neoplastic, which means growing excessively and abnormally. Adrenal adenomas are relatively common benign tumors, as illustrated in incidental findings on imaging done for other medical reasons, such as prenatal ultrasounds or CT (computed tomography) scans to evaluate kidney or gallstone disease. Adenomas have a relatively common frequency, observed in 1 to 32 percent of people in autopsy series (meaning, in random autopsy series of people who died of any cause, incidental adrenal adenomas were found in that many individuals). . To further clarify, most adenomas are termed incidentalomas, meaning they are found incidentally in the body and are generally not life threatening. However, there is a subset of adenomas that secrete hormones that can cause endocrine abnormalities in the body such as Cushing's syndrome.

Unlike the common adenomas, adrenocortical carcinomas (ACCs) occur about 0.0001% (1 in one million of the population per year in the United States). Contrasted with the incidence rate of breast cancer (about 1,300 in one million of the population per year in the United States), adrenocortical carcinomas are rare. Not only are ACCs rare, but they are more challenging to treat and more often ultimately fatal.

There are different types of adrenocortical tumors: benign or malignant, and functioning (they secrete hormones) or nonfunctioning (they do not secrete hormones). Understanding these aspects may help explain the behavior of these tumors.

Nonfunctioning Adenomas

The most common adrenocortical tumors are benign, nonfunctioning, and less than 4 cm in diameter, otherwise called adenomas (masses of excessively growing adrenal epithelial cells). Adenomas are not cancerous or malignant and, therefore, do not metastasize (spread to other tissues or organs).

Functioning Adrenocortical Adenomas

When abnormal amounts of the aforementioned hormones are secreted by functioning tumors, they can cause serious abnormalities in the body. Some effects of functioning tumors include Cushing's syndrome, hyperaldosteronism, (and less commonly) virilization and feminization. Cushing's syndrome occurs when body tissue is exposed to high amounts of cortisol and may lead to hypertension and weakening of bones, muscles, and the immune system. Hyperaldosteronism (Conn's syndrome) is the excess production of aldosterone which may lead to fluid retention, high blood pressure, mineral abnormalities in the body, generalized weakness and even paralysis. Virilization and feminization are the development of more masculine and feminine features, respectively, due to hormone increases, also caused rarely in adrenal abnormalities.

Adrenocortical Carcinoma

The cause of this cancer is unknown. However, it is possibly caused by a preexisting adenoma that becomes malignant, which is thought to be rare, or it may be a de novo occurrence of cancer without having a prior adenoma, meaning sporadic occurrence of a cancer might occur. As previously mentioned, adrenocortical carcinoma (ACC) is an extremely rare cancer, with only one person in one million becoming affected per year in the United States. Functioning ACCs cause the same abnormalities as described above with functioning adenomas, but they occur at a higher frequency relative to nonfunctioning ACCs and, when advanced, may become rapidly fatal, as opposed to adenomas. Some characteristics of ACCs are irregular borders, tumor size larger than 4 cm in diameter, enlarged lymph nodes, and distant metastasis. Distant spreading ACCs generally metastasize to the lungs, liver, bone, and lymph nodes. It remains controversial, however, whether functioning or nonfunctioning tumors are more aggressive.

There are a number of methods that can be used to detect adrenocortical tumors. To begin, doctors will perform a physical examination to check for pain or lumps in abdominal and back regions. To monitor for functional tumors, several blood and urine tests can be performed to see if there are abnormal amounts of hormones and minerals in the body. Imaging studies such as CT, MRI (magnetic resonance imaging), and PET (positron emission tomography) scans also help differentiate between cancerous and noncancerous tumors, in addition to monitoring effects of therapies. Combined PET-CT scanning may provide improved accuracy, but it cannot be relied upon solely for a diagnosis. Ultrasound is another modality that may sometimes demonstrate adrenal tumors. Pathologists are the most appropriate doctors to make the distinction between benign and malignant tumors. Pathologists will review a specimen from a needle biopsy or surgical specimen from the tissue in question, which, once reviewed, is classified as noncancerous or cancerous. If cancerous, the tumor is staged as Stage I (early stage) - Stage IV (most advanced).

• Stage I - tumor less than 5 cm; in adrenal gland
• Stage II - tumor greater than 5 cm; in adrenal gland
• Stage III - tumor of any size; has spread to lymph nodes near adrenal glands
• Stage IV - tumor of any size; has spread to lungs, bones, liver, and/or abdominal wall

Who Gets Adrenocortical Carcinoma?

Some patients have a hereditary genetic predisposition that may be linked to their current cancer, but the vast majority of cases are sporadic. The disease peaks at ages younger than five, as well as in the 40s to 50s. ACC tends to be more aggressive in adults than in children. Interestingly, it has been observed that more women get functioning ACCs, while more men get nonfunctioning ACCs.

What Causes Adrenocortical Carcinoma?

The answer is unknown. There is no known association with smoking, alcohol consumption, or other occupational or environmental exposures. There is a small minority of patients with a hereditary component that may be related to genetic syndromes, such as those with p53 gene abnormalities (the p53 gene codes for a protein which has been demonstrated to be a tumor suppressor protein; ie. when abnormal, the cell may acquire an ability to become cancer).

How Can Adrenocortical Carcinoma Be Treated?

Early stage disease is highly curable through surgical resection of the tumor by specially trained surgical oncologists, such as endocrine surgeons, who specialize in treating this disease. The problem is that many, if not most, ACCs are found at advanced stages.

While there is no curative treatment available for metastatic and recurrent ACC, patients may still benefit from various modalities of therapy.

If the tumor can be fully removed, surgical resection is the primary recommended route. If possible, complete surgical resection is preferred over incomplete resection (higher reported survival rates support this). After surgery, mitotane treatment (a drug therapy) may be utilized to potentially improve cure rates and increase survival. While this is an attractive idea, supportive clinical literature has been quite inconsistent. Some studies showed improved benefit with therapy whereas other studies did not. Probably one of the best studies to date was published by Terzolo et al. (2007). In this study, patients who received postoperative mitotane therapy had higher rates of recurrence-free survival compared with those who did not receive mitotane.

If the tumor is not resected, the patient has the potential to develop distant metastases or advanced adrenocortical carcinoma. Mitotane is also utilized in patients with unresectable tumors of any stage. Potential gastrointestinal and neurological side effects include vomiting, nausea, and anorexia; these can also be attributed to lack of cortisol. Occasionally, the side effects may limit the use of this medicine.

There is a variety of chemotherapies, such as cisplatin, etoposide, doxorubicin, streptozotocin, vinca alkaloids, that can be used to treat ACC. Newer therapies, such as gemcitabine, taxanes, capecitabine, and bevacizumab, maybe utilized, although supportive data are scant. Supportive care may be important, especially for those who have had complete surgical resection of their adrenal gland(s), in the form of hormone-replacement therapy. After a tumor is surgically removed, often hormone deficiency ensues if hormones are not administered to the body. Various hormones and dosages can be given as directed and monitored by an endocrinologist.

For advanced disease, other local modalities of therapies may be pursued in terms of palliating (improving) symptoms. These modalities, including radiation therapy, radiofrequency ablation (RFA), cryotherapy, and nerve ablative techniques, may be important to manage tumor complications of growth. Sometimes RFA or radiation therapy may be administered in the primary management of adrenocortical carcinoma in a particular clinical situation.

The rarity of adrenocortical carcinoma means that the potential opportunities to perform adequate clinical study are limited, which is the obvious reason that there is a paucity of clinical data on this rare disease. Researchers and clinicians caring for patients with this disease are committed to continue studying and working on finding new ways to diagnose, manage, and monitor this disease. An example of a team of physicians dedicated to this challenge is the UCLA endocrine surgery team. Any patient with this rare disease should be encouraged to seek, at minimum, evaluation at a center like UCLA's, which is dedicated to treatment of these rare tumors.

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