Adrenal Tumors and Cancer

In order to understand adrenal cancer and adrenal tumors, it's important to learn about the adrenal gland, in general.

What Are the Adrenal Glands?

Each person is usually born with two adrenal glands. The adrenals are paired, goldenrod-yellow colored glands that are situated behind the organs of the gastrointestinal tract next to the spine and just above the kidneys in a space called the retroperitoneum.

The two adrenal glands are responsible for making hormones -- substances that make other cells in the body respond in various ways. These hormones enable the body to respond to stress, regulate blood pressure and the amount of fluid in the body, and are involved in the regulation of electrolytes such as sodium and potassium.

The hormones produced by the adrenal glands include aldosterone, cortisol, epinephrine and norepinephrine. The adrenal glands also make small amounts of the sex hormones testosterone and estrogen. The ovaries and testicles make the majority of sex hormones. When certain cells in the adrenal glands produce too much of any one of the hormones, abnormalities can result which may affect many organ systems of the body. Disturbances in the amount of hormone produced can be the result of all cells in the gland producing too much hormone (hyperplasia) or be the result of a few cells, a nodule or mass within an otherwise normal gland, producing too much hormone.

Adrenal Cancer: Disease Overview

Adrenal tumors are classified by their growth characteristics:

Adrenal adenoma - adrenal tumor that is benign
Adrenal carcinoma - adrenal tumor that is malignant (cancer)

Adrenal cancer (adrenocortical carcinoma or ACC) is an extremely rare cancer which occurs in 1-2 people per million people in the population. Approximately 600 patients are diagnosed with adrenal cancer each year in the United States.

At the University of Michigan, we are constantly making progress and strive to improve outcomes for our patients.

For those patients diagnosed with a disease as rare as adrenal cancer, it is important to seek medical advice at a center which specializes in this particular type of cancer. Despite increased utilization of imaging studies, ACC is not being identified at earlier stages in the United States. For various reasons, patients with ACC do not usually present for medical evaluation until late in the disease process. In adults, adrenal cancer often has no obvious symptoms, which makes it difficult to diagnose in its early stages. Those patients who have tumors that produce excess adrenal hormones tend to be diagnosed earlier in the disease process. The most common hormone produced by adrenal cancers is cortisol. This may lead to Cushing’s syndrome. Testosterone is another hormone commonly secreted by adrenal cancers. This may lead to development of a virilizing syndrome. Aldosterone producing adrenal cancers are extremely rare but do occur and can lead to the development of Conn syndrome.

Unfortunately, the majority of patients with ACC present with advanced disease, and many are diagnosed at a point when surgery is no longer feasible. These patients are treated with medications to help minimize (palliate) any symptoms they might have, and chemotherapy or radiation therapy may be offered. The Endocrine Oncology Clinic offers a multidisciplinary approach with expertise in endocrinology, endocrine surgery, chemotherapy and radiation therapy to offer patients the highest standard of care. In addition, we work very closely with the University of Michigan Phase I trial center to offer our patients the option of participating in a clinical study using medications that result from decades of adrenal cancer research at the University of Michigan and other institutions.

For those patients who are diagnosed with adrenal cancer at a point in time where surgery is possible, complete surgical resection of all tumor currently provides the only opportunity for cure or long-term survival from ACC and is the treatment of choice. However, surgery with curative intent is not the only indication for surgical intervention in the patient diagnosed with ACC. In those patients with tumors producing excess hormone and suffer severe hypertension, hypokalemia, or severe effects from steroid (cortisol) excess which cannot easily be controlled with medication, surgery may be worthwhile to help decrease the symptoms of hormone excess even if distant metastatic disease is present.

In the United States, forty-five percent of adrenalectomies for ACC are performed in community hospitals, 30% in academic centers, and only 15% in hospitals designated as a National Cancer Institute (NCI) designated cancer center. The University of Michigan Rogel Cancer Center is an NCI designated cancer center. Overall there is good evidence that treatment at specialized centers improves patient outcome in terms of cure and survival.

Adrenocortical cancers are often aggressive and can spread to other parts of the body (metastasize) rapidly. The adrenal gland is one of the most vascular organs in the body, with many blood vessels that can carry malignant cells throughout the body. Because the adrenal gland resides behind the intestines and other abdominal organs, it can grow to a very large size before causing any sort of local compressive symptoms or pain. This explains why it is difficult to identify these tumors early on in the disease process, especially if they do not happen to produce any excess amount of adrenal hormones. Unfortunately, symptoms due to adrenal hormone secretion, such as high blood pressure, weight gain, and diabetes are common conditions in middle-aged adults, so the possible connection with an adrenal tumor is often overlooked. The speed of onset of these signs and symptoms may in retrospect be helpful in determining when the tumor started growing. If these conditions develop rapidly, they can be warning signs of adrenal cancer; however, if the adrenal tumor is slow-growing and non-functional (meaning it does not produce excess adrenal hormones), there are usually no symptoms noted in early stages of the disease. As the tumor grows, it may begin to cause local symptoms as it compresses or invades into other organs. In many cases, imaging studies (CT scans) are obtained for vague symptoms that most physicians think are related to a different organ (stomach, gallbladder, pancreas, colon, chronic low back pain) or disease process.

Adrenal Tumors

Conn's Syndrome, also known as Aldosteronoma/Primary Hyperaldosteronism

An aldosteronoma is an adrenal tumor which makes excess amounts of aldosterone. Aldosterone normally helps regulate fluid status in the body, sodium and potassium levels, and affects blood pressure. When excess aldosterone is produced by the adrenal glands or an adrenal nodule, patients often present to their physician with new elevation of blood pressure (hypertension) and low potassium (about 40% of patients). University of Michigan's preeminence in the field dates back seven decades to the appointment of Dr. Jerome Conn as director of the University of Michigan Metabolism Research Unit in 1943. Dr. Conn was the first to identify findings associated with excess aldosterone production. This constellation of findings is now known as Conn's syndrome.

Diagnosis of primary hyperaldosteronism is confirmed by having an elevated aldosterone level and decreased renin level with an aldosterone:renin ratio of at least 20:1. Diagnosis is inferred from laboratory work. Imaging is then obtained, if not already performed, and in most cases adrenal vein sampling (an interventional radiology procedure) is performed. Adrenal vein sampling identifies from which adrenal gland excess aldosterone is coming from. In some patients, both adrenal glands are producing too much aldosterone. These patients are treated with medications such as spironolactone, aldactone, or eplerenone as it is not desirable to remove both adrenal glands in most patients.

For patients with excess aldosterone production from one gland, surgery is usually proposed. Most surgeries can be performed by a laparoscopic approach (minimally invasive) through several small incisions. The vast majority of aldosterone producing nodules are benign, but in very rare cases, these nodules can be malignant. Most aldosteronomas are no more than 1-2 centimeters in size. Malignant aldosterone producing adrenocortical carcinomas should be considered when nodule size reaches greater than 3 to 3.5 centimeters, which is lower than the concern cutoff of malignancy for adrenal nodules in general (4 centimeters at University of Michigan, 6 centimeters in some centers).

Cushing's Syndrome

Cushing’s syndrome may be caused by an adrenal tumor which makes excessive cortisol (a steroid) or by another type of tumor (often lung or a different type of neuroendocrine tumor) that makes adrenocorticotropic hormone (ACTH). Patients often present with new hypertension, diabetes, central obesity (big belly, skinny arms and legs), easy bruising, purplish lines on the abdomen, round "moon" face, flushed face, increased fat near the collar bones, worsening blood sugar control (diabetes), thin skin. Most patients notice a significant difference in their appearance when viewing photographs of themselves that are several years old.

Similarly, Cushing's Disease (as opposed to Syndrome) is caused by a pituitary tumor which causes both adrenal glands to produce excess cortisol. Most patient with Cushing's syndrome have benign (non-cancerous) adrenal nodules. Adrenocortical cancers can (not always) produce excess amounts of hormones, with cortisol being the most common hormone secreted. Imaging characteristics of the nodule/tumor are also usually concerning for malignancy in these cases of cortisol producing adrenal cancers.

Pheochromocytoma and Paraganglioma

An adrenal tumor making excess amounts of adrenaline (epinephrine, norepinephrine, and in very rare cases dopamine). These substances are referred to as catecholamines. Patients with adrenal nodules producing excess amounts of catecholamines often present with new/worsening hypertension, headaches, sweating, palpitations (racing heart), flushing, and panic attacks. Blood pressure elevations can be so severe that they can lead to heart attacks, stroke and sudden death. Patients with pheochromocytomas may have a genetic syndrome. About 30% of pheochromocytomas and the majority of paragangliomas are arising in patients with a hereditary predisposition syndrome, meaning they carry genetic changes inherited from their parents. Therefore everybody with a diagnosis of pheochromocytoma or paraganglioma should have an evaluation by a genetic counselor as part of a multidisciplinary clinic visit or in the Cancer Genetics Clinic.

Malignant (cancerous) pheochromocytomas occur in approximately 10% of patients. Those with benign pheochromocytomas are usually offered laparoscopic surgery performed through several small incisions, while those with malignant appearing or very large tumors are offered surgery using an open approach performed through a larger incision. Malignant tumors are diagnosed when there is evidence of tumor invasion into surrounding tissue or organs, involvement of lymph nodes, or evidence of distant metastatic disease.

Paragangliomas are tumors which are very similar to pheochromocytomas. They produce excess norepinephrine and occur outside the adrenal gland. They may occur anywhere along the side of the spine from the neck to the pelvis. Some catecholamine producing tumors are found inside the bladder and may cause symptoms when patients urinate as the bladder contracts.

Prior to surgery, it is extremely important that the blood pressure be well controlled using certain medications called alpha blockers, beta blockers, and on occasion calcium channel blockers. Alpha blockers (such as dibenzyline) should always be started before beta blockers (such as metoprolol, propranolol, or other medications in the same class) in order to prevent cardiac collapse. Medications to control the blood pressure and heart rate are increased until patients achieve blood pressure goals and also if they have symptoms of nasal stuffiness and slight dizziness upon initially standing. If these goals are not met prior to surgery, the blood pressure may become dangerously high during surgery as the tumor is manipulated and lead to heart attacks, strokes, and increased bleeding.

For more information, download and/or print the Pheochromocytoma/Paragangnglioma (PCC/PGL) Brochure [pdf]

Virilizing and Feminizing Adrenal Tumors

Tumors of this type are rare and some are associated with adrenocortical carcinomas. A virilizing adrenal tumor makes excess androgens (testosterone). Patients often present with increased hair growth (hirsutism), increased muscle mass, acne and amenorrhea (loss of periods in a female). A feminizing adrenal tumor makes excess estrogen. Patients often present with increased growth of breast tissue (gynecomastia/breast growth in men) and impotence may be experienced by men.

Congential Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a group of genetic disorders affecting the adrenal glands. Although CAH is not a cancer, but an inherited condition, patients are seen by our adrenal specialists in the Multidisciplinary Endocrine Oncology Clinic. CAH patients have a defect in one of the enzymes that are necessary to produce adrenal hormones and most often will have low cortisol levels. They also have often very high blood levels of other steroids that are produced by the adrenal gland, which act like male sex hormones. In women this leads to masculinization either at birth (severe condition) or may lead to male changes and infertility later in life. Patients with CAH need a physician that is familiar with the condition to guide them through therapy and hormone replacement therapy with adrenal hormones.

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