Adrenocortical Tumors and Cancer
The adrenal glands are an important part of the endocrine system of the human
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
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.
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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
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.
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
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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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1. J. Kimball. Kimball's Biology Pages. "The Adrenal Glands." September 15,
2005. As of June 17, 2008:
2. EndocrineWeb.com. 1997-2002. As of June 17, 2008:
3. Chew, S. "Adrenal Adenomas." Netdoctor.co.uk. January 8, 2005. As of June
4. Imaginis.com. "General Information on Breast Cancer." Updated January 23,
2008. As of June 17, 2008:
5. The Merck Manuals: Online Medical Library. "Hyperaldosteronism." rev. November
2007. As of June 17, 2008:
6. National Institutes of Health. National Institute of Diabetes and Digestive and Kidney
Diseases. National Endocrine and Metabolic Diseases Information Service. "Cushing's
Syndrome." NIH Publication No. 02-3007.?June 2002. As of June 17, 2008:
7. Terzolo et al. Adjuvant Mitotane Treatment for Adrenocortical carcinoma, New England
Journal of Medicine, 2007, Vol. 356:pp2372-2380.
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