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Adrenal Disease

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 Nodules

Adrenal nodules are found in approximately 5-8% of all patients. The vast majority are benign (non-cancerous) and do not produce excess amounts of hormone. Most adrenal nodules do not cause any symptoms and are found only when imaging studies (CT scans, MRIs) are obtained to evaluate symptoms related to another problem. When a patient is found to have an adrenal nodule, a systematic approach should be followed to further evaluate the nodule. Evaluation of an adrenal abnormality found on imaging is done to ensure two things: 1) the nodule has benign imaging characteristics (make sure the nodule doesn't look like an adrenal cancer), and 2) ensure no evidence of hormone excess (make sure the nodule is producing too much of the hormones it normally produces).

An appropriate evaluation of a newly found adrenal nodule includes obtaining a CT scan or MRI done specifically to look at the adrenal glands. At University of Michigan, our team prefers to investigate adrenal abnormalities using CT first, and MRI if a different type of study is needed. Patients also have blood drawn and submit urine samples (drawn over 24 hours) to test for excess amounts of adrenal hormones. Other laboratory studies may be obtained depending on individual patient findings. If patients are found to have a benign appearing nodule by imaging and no evidence of excess hormone production, patients are scheduled for a follow-up CT scan in 6 months. Continued follow-up after this, if no changes in imaging characteristics are noted on the follow-up scan, range from no further follow-up (nodule is considered benign and does not need to be followed) to imaging and biochemical/laboratory testing for five years.

If an adrenal nodule does not meet imaging criteria that is considered benign, surgery is recommended.

Biopsy of the adrenal gland is not recommended except in highly specific instances. Biopsy may be appropriate if there is significant concern that an adrenal abnormality is the result of metastatic disease from another source when no other site of metastatic disease can be accessed for a biopsy. Biopsy of a pheochromocytoma [adrenal nodule producing adrenaline (epinephrine, norepinephrine, or dopamine)] is extremely dangerous and should not be done, as this can lead to extreme elevations in blood pressure and cause a stroke or heart attack. Biopsy of an adrenal mass not meeting imaging criteria for a benign process leads to recommendation for surgery regardless, and biopsy is not indicated. Puncture of an adrenal cancer by a needle or other instrument can potentially lead to increased recurrence at the site of the tumor after removal of the gland and decrease the chance for cure. It is extremely difficult for pathologists to differentiate a benign adrenal tumor from a malignant adrenal tumor from tissue obtained by a needle biopsy. Seek a second opinion if someone has recommended you have your adrenal nodule/mass biopsied.

If laboratory studies/bloodwork show evidence of excess hormone production, further evaluation is pursued to determine what hormone is being produced and which gland is producing the excess hormone as not all excess hormone production comes from the nodule seen on imaging. Sometimes, the nodule is not producing excess hormone, but the entire gland (or both glands) may be responsible for producing too much of a particular hormone.

Aldosteronoma/Primary Hyperaldosteronism (Conn's Syndrome)

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 their blood pressure (hypertension) and low potassium (about 40% of patients). U-M's preeminence in the field dates back seven decades to the appointment of Dr. Jerome Conn as director of the U-M 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 by 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.

In patients who have excess aldosterone production from one gland, surgery is offered. 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 cutoff for concern for malignancy for adrenal nodules in general (4 centimeters at U-M, 6 centimeters in some centers).

Cushing's Syndrome

An adrenal tumor which makes excessive cortisol (a steroid). 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 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.


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. All patients diagnosed with a pheochromocytoma who are seen in the U-M Multidisciplinary Endocrine Oncology clinic are also seen by one of our genetic counselors and may be referred for further genetic testing. 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 malignancy 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.

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 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.

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 (hirsuitism), 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 in men.

Adrenal Cancer

Adrenal tumors are classified by their growth characteristics:

  • Adrenal adenoma - adrenal tumor that is benign
  • Adrenal carcinoma - adrenal tumor that is malignant

Adrenal cancer (adrenocortical carcinoma or ACC) is an extremely rare cancer that occurs in 1-2 people per million people in the population. Approximately 600 new cases per year are diagnosed in the United States.

A recent study revealed that in the past twenty years no significant progress has been made with regard to the treatment of ACC, and 5-year survival outcomes have remained static. In the United States, forty-five percent of adrenalectomies for ACC are performed in community hospitals, 30% in academic centers, and only 15% in National Cancer Institute designated cancer centers. Despite increased utilization of imaging studies, ACC is not being identified at earlier stages in the United States; however, at select quarternary referral centers, it does appear that there may be some progress being made in terms of treatment. For various reasons, those with ACC do not usually present until late in the disease process. In adults, adrenal cancer usually has no obvious symptoms, which makes it very hard to diagnose in its early stages. Those patient who have tumors that produce excess adrenal hormones tend to present earlier on in the disease process. The most common hormone produced by adrenal cancers is cortisol. Testosterone is another more commonly secreted hormone by adrenal cancers. Aldosterone producing adrenal cancers are extremely rare but do occur.

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. 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. Surgery for curative intent is not the only indication for surgical intervention in the patient diagnosed with ACC. In those patients who have tumors that produce excess hormone levels and suffer severe hypertension, hypokalemia, or severe effects from steroid (cortisol) excess, surgery may be worthwhile to help decrease the symptoms of hormone excess even if distant metastatic disease is present.

Adrenocortical carcinomas are usually 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 in the retroperitoneum (surrounded in fat and residing behind the intestines and other abdominal organs), it can grow to a very large size before causing any sort of local compressive symptoms. 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, 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).

Treatment of Adrenal Cancer

Surgery is the treatment of choice if possible. In many cases, patients present after tumor has spread to other organs in the body or the tumor has invaded structures that cannot be removed and the tumor is considered inoperable. If patients are able to undergo surgery, it is extremely important that your surgery is performed by a surgeon experienced in the treatment of adrenal cancer (most surgeons see one adrenal cancer patient in a lifetime), as the covering of the tumor must not be penetrated during surgery and a wide margin of normal tissue around the tumor should be included to ensure complete resection and minimize the chance for local recurrence. Appropriate preoperative evaluation and planning is of the utmost importance in adrenal cancer patients to assure optimal outcome. Adrenal cancer is a very rare cancer different from many other types of cancers. It must be carefully and completely removed. Based on recent research at the University of Michigan, it is not recommended to have adrenal cancer (or any mass/nodule suspected of potentially being malignant) removed laparoscopically. It is thought that laparoscopic instruments rub against the tumor and spread tumor cells to other parts of the abdomen leading to early recurrence. More often, the entire tumor is not resected when the procedure is performed laparoscopically, and the "margins" (edges of the tissue removed) are positive for tumor cells. An open approach (through a larger incision along the rib cage or along the midline of the abdomen) allows the surgeon to remove a rim of normal (benign) tissue around the tumor more easily to help decrease rates of recurrence.

Unfortunately, even with pathologically documented complete resection of ACC, up to two-thirds of patients have recurrence of tumor in a locoregional or distant site, or both. Individual markers of tumor biology such as histologic grade, length of disease-free interval, and slow progression of tumor can be used as a guide when considering re-operation. If a resectable local recurrence presents without evidence of distant metastases, re-operation is associated with increased length of survival when compared to patients treated with chemotherapy alone. In patients with excess hormone secretion and difficulty controlling symptoms related to the excess hormone secretion, surgery may be offered to debulk the tumor in hopes of decreasing the hormone levels. Consideration for reoperative surgery in these patients with evidence of metastatic disease and severe symptoms from hormone excess may be helpful depending on the amount of existing tumor and amount of tumor that will be able to be removed and is made on a case by case basis.

Treatment After Adrenal Cancer Surgery

After surgery, the U-M multidisciplinary tumor board will review the intraoperative findings and the pathology report. Important aspects of the pathology report include completeness of resection and margin status (positive or negative), capsular or vascular invasion, tumor grade (low or high), evidence of tumor within lymph nodes, or invasion of nearby structures. Decisions regarding further treatment are made. Treatment may include one or more of the following: external beam radiation therapy, mitotane, and/or chemotherapy. If mitotane is started, labs to check mitotane levels, thyroid function and liver function will be checked frequently and replacement steroids will also be started.

Follow-up Care

Clinic visits, imaging studies, and blood work are obtained at least every three months to assess disease status and look for evidence of recurrence or disease progression. U-M physicians will work closely with a patient's primary care physician and other physicians near their home to ensure they are receiving optimal care. For those with persistent or recurrent disease, U-M physicians will aggressively pursue all treatment options and stay abreast of new clinical trials offered around the world.

Adrenal Cancer Outcomes

In general, five year survival rates for all patients diagnosed with adrenocortical carcinoma approaches 50%. When including those unable to undergo surgery, five year survival rates decrease to approximately 35%. Five year survival rates are different depending on the Stage of the tumor. There are four stages based on the size of the tumor, invasion of nearby structures, involvement of lymph nodes and evidence of distant metastatic disease. Survival according to Stage is most favorable for patients with Stage I disease and worst for those with Stage IV (distant metastases) disease. Available percentages for overall survival and for survival according to stage should be viewed with caution, as individual tumor characteristics, adequate surgery, and appropriate follow-up and adjuvant treatment (chemotherapy and radiation) all affect outcome. U-M endocrine oncology team members treat patients with adrenal cancer aggressively and with state of the art techniques and pursue new therapies to provide patients with the best care possible and best chances for survival.

Lifestyle Risks

Because adrenal cancer is more common in some countries than others, scientists used to wonder if something in the environment might be causing people to develop adrenal cancer. This may be the case in some patients, but likely not for the majority of patients. Today, most scientists believe adrenal cancer is caused by genetic mutations, but how environmental factors might influence the disease is still unclear.

Sometimes patients wonder if stress causes adrenal cancer since the adrenal gland is part of the body's system for handling stress (physical). The adrenal glands make cortisol and catecholamines (epinephrine and norepinephrine), both hormones involved in the "fight or flight" response. These hormones allow the body to respond to stressful situations (serious illness, trauma, etc.). There is no scientific evidence that increased stress (mental or physical) causes adrenal cancer.

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