Adrenocortical Carcinoma

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Key Terms: Biopsy, Carcinoma, Computed tomography, Homeostasis, Hormone, Inferior vena cava, Lymph nodes, Magnetic resonance imaging, Pituitary.

Definition

Adrenocortical carcinoma is a malignant growth that originates in the cortex, or the outer portion, of one of the two adrenal glands.

Description

There are two adrenal glands in the body. Each one is paired with a kidney. The adrenal gland rests atop the kidney, on the side of the kidney that is nearest to the head.

An adrenal gland has two parts. The inner part (medulla) produces hormones such as epinephrine (adrenaline) that increases the heart rate. The cortex, or outer part, is made up of layers of epithelial cells, the cells that form coverings for the surfaces of the body. The cortex produces cortical hormones that are essential to well being, or homeostasis.

The hormones produced by the cortex include glucocorticoids, mineralocorticoids, and sex hormones. Among the many hormones the cortex makes, three—aldosterone, cortisol and adrenal sex hormones—are very important. Aldosterone helps regulate salt and water content in the body. Cortisol helps keep sugars, fats and proteins in balance. Adrenal sex hormones influence sex organ development and sex drive (libido).

Adrenocortical carcinoma is a cancer that originates in the cortex of the adrenal gland. When a tumor grows in the adrenal cortex, it interferes with the production of hormones. Consequently, the effects of adrenocortical carcinoma can be severe and are almost always a threat to life.

There are two types of adrenocortical carcinoma. In one type, a tumor functions—that is, it makes hormones. In the other type, the tumor does not function. If the tumor functions, it acts like the cells in the cortex from which it grew and thus, produces hormones. But since it grows large, it produces extra amounts of hormones and the body is thrown far out of balance in any one of a number of ways.

When a Tumor Functions

How excess hormones cause the symptoms they produce is complex because more than one hormone from the adrenal cortex can be involved in producing a single symptom. For example, both aldosterone and cortisol, when present in extra quantities, may contribute to the increase in blood pressure (hypertension) many patients experience. Extra amounts of adrenal sex hormones can cause children to begin to display the sexual characteristics (hair growth, genital maturation) of adults. And adults with extra amounts of sex hormones often begin to display the sexual characteristics of the opposite sex. A woman may grow excess facial hair. A man may begin to develop fatty tissue in his breasts. Large quantities of adrenal sex hormones coursing through the body disrupt what would be a normal loop of feedback from the pituitary area of the brain. The pituitary is geared to send information, via a stimulating hormone, to the adrenal cortex, to prompt the tissue to manufacture adrenal sex hormone. When there is an extra amount of adrenal sex hormone in the body, the pituitary stops sending instructions to the adrenal cortex, as well as to other organs that produce the hormones responsible for male features. Thus, a man can begin to look like a woman because he does not have enough male hormones. A woman can begin to look like a man because she has too much adrenal sex hormone.

When a Tumor Does Not Function

If the tumor does not function, it just grows large, and may go unnoticed for a long time. Sometimes a tumor that does not function is called dormant. Often, the tumor that does not function first gets attention when it grows large enough to push against the body wall or an organ and cause pain; or when it has spread (metastasized) to another organ.

The adrenocortical carcinoma that does not function has a high likelihood of metastasizing before it is discovered. The two most common sites for metastases are the lungs and liver. Thus, even a non-functioning tumor may cause serious complications.

Demographics

Adrenocortical carcinoma is rare. Fewer than two in one million people, and perhaps as few as one in four million people, are diagnosed in a year. Two age groups are most likely to be diagnosed: those between zero and ten years of age, and those between 40 and 50 years.

Causes and Symptoms

Causes

The cause of adrenocortical carcinoma is not known. Infection with bacteria or parasites is linked to other conditions of the adrenal glands, and there could be a connection with adrenocortical carcinoma. There is also evidence that adrenocortical carcinoma in children is caused by some chemical to which they were exposed as fetuses—possibly a chemical that the women carrying the children were exposed to in food, drink, or in the air.

Many tumors of the adrenal cortex have cells with extra copies of chromosomes, the beads of genetic material or DNA. Chemicals in the environment that are known to affect cells and cause mutations are being investigated as possible causes for adrenocortical carcinoma.

Symptoms

Depending on whether or not the tumor interferes with the production of hormones, the tumor may or may not be linked to symptoms during its early growth. A group of Japanese surgeons led by K. Kunieda reported the case of a 52-year-old man who had a tumor weighing more than two pounds at the time it was discovered. The tumor had not been producing extra hormones, and was not producing symptoms.

An adrenocortical tumor that functions produces many symptoms. Some of them are similar to those linked to other conditions, and many of these conditions have names that are based on a collection of symptoms and not on the cause. A combination of the following symptoms, known as Cushing's syndrome, could be caused by a tumor in the pituitary area of the brain, as well as by adrenocortical carcinoma:

• an abnormal accumulation of fatty pads in the face (creating the distinctive "moon face" of Cushing's syndrome); in the trunk (termed "truncal obesity"); and over the upper back and the back of the neck (giving the individual what has been called a "buffalo hump")
• purple and pink stretch marks across the abdomen and flanks
• high blood pressure
• weak, thinning bones (osteoporosis)
• muscle atrophy (due to protein loss)
• low energy
• thin, fragile skin, with a tendency toward both bruising and slow healing
• abnormalities in the processing of sugars (glucose), with occasional development of actual diabetes
• increased risk of infections
• irregular menstrual periods in women
• decreased sex drive in men and difficulty maintaining an erection
• abormal hair growth in women (in a male pattern, such as in the beard and mustache area), as well as loss of hair from the head (receding hair line)

Similarly, virilization syndrome, or the tendency of a child to exhibit adult sexual features, or a female adult to exhibit male features, can be caused by other conditions, such as tumors in the pituitary, or by adrenocortical carcinoma. So, too, with feminization, or the tendency of a male individual to exhibit female characteristics, such as enlarged breasts and fat deposits on the hips.

Diagnosis

Symptoms usually cause a patient to talk with a physician. Blood and urine samples are examined to learn whether hormones are out of balance. Venography, a way of getting a picture of the inside of veins, is a technique that is still used to examine the adrenal glands prior to any decision about surgery. But the magnetic resonance imaging (MRI) scan has replaced venography in many facilities. Computed tomography (CT) scan is also used to examine the adrenal cortex.

Treatment Team

Depending on symptoms, the first specialized physician an individual consults may either be an endocrinologist (a physician who focuses on hormones) or a urologist (a physician who focuses on the study of the kidneys and nearby structures). Either one of them, or a medical oncologist (a physician who focuses on treating patients with cancer) will lead the treatment team. A surgeon will be on the team too because in almost all cases removal of the adrenocortical carcinoma to the fullest extent possible is standard procedure.

Nurses will be on the team to help with administering drugs and monitoring the status of the patient. And if the patient is given chemotherapy, technicians skilled in the treatment will be part of the team.

Clinical Staging, Treatments, and Prognosis

Adrenocortical tumors are assigned to one of four stages.

• Stage I tumors have not spread beyond the cortex of the adrenal gland and are less than two in (5 cm) in their greatest dimension.
• Stage II tumors have not spread beyond the cortex of the adrenal gland and are more than two inches.
• Stage III tumors have either spread into tissues around the adrenal cortex or they have spread into lymph nodes near the adrenal glands, or both.
• Stage IV tumors have spread to lymph nodes and other organs near the adrenal cortex or to other organs of the body.

A plan for treatment is based on the size and extent of the tumor. Surgical removal of the tumor, radiation and chemotherapy are all used. Method of treatment depends on how large the carcinoma is and whether it has spread to other organs. In some cases the treatment is strictly palliative (provides comfort) and is not expected to halt the course of the cancer. Palliative treatment can include surgery to reduce the size of the tumor, as well the pain a large tumor causes by pushing against other organs.

Because adrenocortical carcinoma that metastasizes often moves into the renal (kidney) vein and then, the inferior vena cava, venography or MRI scan prior to surgical removal of all or part of the tumor is important. If the tumor has grown into a vein, a piece of it can be dislodged and become a dangerous object. The piece of tumor begins to move in the blood flow and it is capable of getting stuck in a small blood vessel in the heart or the brain, and causing a stroke.

The drug mitotane gives some good results is slowing tumor growth in certain patients. But the only therapy that provides relief in most patients is the removal of the tumor.

The outlook for individuals with adrenocortical carcinoma depends on the stage of the cancer. Because seven in ten individuals are diagnosed only after the cancer has reached stage III or stage IV the five-year survival rate for all stages is 40%. And for individuals with stage IV carcinoma it is much less, with most patients dying within nine months of diagnosis.

Alternative and Complementary Therapies

Yoga, biofeedback or other relaxation techniques may help manage pain.

Coping With Cancer Treatment

Being an active member of the treatment team is important. Premier cancer centers encourage patients to play such a role. A support group can also help.

Clinical Trials

The Cancer Information Service at the National Institutes of Health, Bethesda, Md., offers information about clinical trials that are looking for volunteers. The Service offers a toll-free number at 1-800-422-6237.

Prevention

No prevention is known.

Questions to Ask the Doctor

• In which stage is the carcinoma?
• With this type of carcinoma, what is the five-year survival rate for a person of my age and gender? What is the one-year survival rate?
• Is there a center that specializes in treating this type of cancer?
• Are there any clinical trials in which I might be eligible to participate?
• Does this health care institution have a support group for individuals with my type of carcinoma?
• What is your approach to relieving pain? (Do we agree?)

Special Concerns

The excess production of hormones that indicate functioning tumors in adrenocortical carcinoma can also be symptoms of other conditions. A tumor in the pituitary gland can cause the pituitary to produce too much of the hormone that stimulates the adrenal cortex to make cortical hormones. The symptoms are identical to those for the adrenocortical tumor. A pituitary tumor must sometimes be ruled out when an adrenocortical carcinoma is suspected. Brain scans may be necessary.

Resources

Periodicals

Kunieda, K., et al. "Recurrence of giant adrenocortical carcinoma in the contralateral adrenal gland 6 years after surgery." Surgery Today 30 (March 2000): 294-7.

Wajchenber, B. L., et al. "Adrenocortical carcinoma: clinical and laboratory observations." Cancer 88 (February 15, 2000): 711-36.

—Diane M. Calabrese

Adrenocortical carcinoma
Classification & external resources

Metastasis of an adrenocortical carcinoma to the lung
ICD-10	C74.0
ICD-9	194
eMedicine	ped/41

Adrenocortical carcinoma, also adrenal cortical carcinoma (ACC) and adrenal cortex cancer, is an aggressive cancer originating in the cortex (steroid hormone-producing tissue) of the adrenal gland. Adrenocortical carcinoma is a rare tumor, with incidence of 1-2 per million population annually.^[1][2] Adrenocortical carcinoma has a bimodal distribution by age, with cases clustering in children under 6, and in adults 30-40 years old.^[1] Adenocortical carcinoma is remarkable for the many hormonal syndromes which can occur in patients with steroid hormone-producing ("functional") tumors, including Cushing's syndrome, Conn syndrome, virilization, and feminization. Adrenocortical carcinoma has often invaded nearby tissues or metastasized to distant organs at the time of diagnosis, and the overall 5-year survival rate is only 20-35%.^[1]

Signs and Symptoms

Adrenocortical carcinoma may present differently in children and adults. Most tumors in children are functional, and virilization is by far the most common presenting symptom, followed by Cushing's syndrome and precocious puberty. ^[1] Among adults presenting with hormonal syndromes, Cushing's syndrome alone is most common, followed by mixed Cushing's and virilization (glucocorticoid and androgen overproduction). Feminization and Conn syndrome (mineralcorticoid excess) occur in less than 10% of cases. Rarely, pheochromocytoma-like hypersecretion of catecholamines has been reported in adrenocortical cancers.^[3] Non-functional tumors (about 40%, authorities vary) usually present with abdominal or flank pain, or they may be asymptomatic and detected incidentally.^[2]

All patients with suspected adrenocortical carcinoma should be carefully evaluated for signs and symptoms of hormonal syndromes. For Cushing's syndrome (glucocorticoid excess) these include weight gain, muscle wasting, purple lines on the abdomen, a fatty "buffalo hump" on the neck, a "moonlike" face, and thinning, fragile skin. Virilism (androgen excess) is most obvious in women, and may produce excess facial and body hair, acne, enlargement of the clitoris, deepening of the voice, coarsening of facial features, and cessation of menstruation. Conn syndrome (mineralcorticoid excess) is marked by high blood pressure, which can result in headache, and hypokalemia (low serum potassium), which can produce muscle weakness, confusion, and palpitations. low plasma renin activity, and high serum aldosterone. Feminization (estrogen excess) is most readily noted in men, and includes breast enlargement, decreased libido and impotence.^[1][2][4]

Diagnosis

Laboratory findings

Hormonal syndromes should be confirmed with laboratory testing. Laboratory findings in Cushing syndrome include increased serum glucose (blood sugar) and increased urine cortisol. Adrenal virilism is confirmed by the finding of an excess of serum androstenedione and dehydroepiandrosterone. Findings in Conn syndrome include low serum potassium, low plasma renin activity, and high serum aldosterone. Feminization is confirmed with the finding of excess serum estrogen

Radiology

Radiological studies of the abdomen, such as CT scans and magnetic resonance imaging are useful for identifying the site of the tumor, differentiating it from other diseases, such as adrenocortical adenoma, and determining the extent of invasion of the tumor into surrounding organs and tissues. CT scans of the chest and bone scans are routinely performed to look for metastases to the lungs and bones respectively. These studies are critical in determining whether or not the tumor can be surgically removed, the only potential cure at this time.^[2]

Pathology

Adrenal tumors are often not biopsied prior to surgery, so diagnosis is confirmed on examination of the surgical specimen by a pathologist. Grossly, adrenocortical carcinomas are often large, with a tan-yellow cut surface, and areas of hemorrhage and necrosis. On microscopic examination, the tumor usually displays sheets of atypical cells with some resemblance to the cells of the normal adrenal cortex. The presence of invasion and mitotic activity help differentiate small cancers from adrenocortical adenomas.^[3] There are several relatively rare variants of adrenal cortical carcinoma: Oncocytic adrenal cortical carcinoma, Myxoid adrenal cortical carcinoma, Carcinosarcoma, Adenosquamous adrenocortical carcinoma, Clear cell adrenal cortical carcinoma.

Differential diagnosis includes: Adrenocortical adenoma, Renal cell carcinoma, Adrenal medullary tumors, Hepatocellular carcinoma.

Treatment

The only curative treatment is complete surgical excision of the tumor, which can be performed even in the case of invasion into large blood vessells, such as the renal vein or inferior vena cava. The 5-year survival rate after successful surgery is 50-60%, but unfortunately, a large percentage of patients are not surgical candidates. Radiation therapy and radiofrequency ablation may be used for palliation in patients who are not surgical candidates.^[1]

Chemotherapy regimens typically include the drug mitotane, an inhibitor of steroid synthesis which is toxic to cells of the adrenal cortex,^[5] as well as standard cytotoxic drugs. One widely used regimen consists of cisplatin, doxorubicin, etoposide) and mitotane. The endocrine cell toxin streptozotocin has also been included in some treatment protocols. Chemotherapy may be given to patients with unresectable disease, to shrink the tumor prior to surgery (neoadjuvant chemotherapy), or in an attempt to eliminate microscopic residual disease after surgery (adjuvant chemotherapy).^[1]

Hormonal therapy with steroid synthesis inhibitors such as aminoglutethimide may be used in a palliative manner to reduce the symptoms of hormonal syndromes.^[1]

Prognosis

ACC, generally, carries a poor prognosis^[6] and is unlike most tumours of the adrenal cortex, which are benign (adenomas) and only occasionally cause Cushing's syndrome. Five-year disease-free survival for a complete resection of a stage I-III ACC is approximately 30%.^[6] The most important prognostic factors are age of the patient and stage of the tumor. Poor prognostic factors: mitotic activity, venous invasion, weight of 50g+; diameter of 6.5 cm+, Ki-67/MIB1 labeling index of 4%+, p53+.

References

1. ^ ^{a b c d e f g h} edited by Vincent T. DeVita, Samuel Hellman, Steven A. Rosenberg (2005). Cancer: principles & practice of oncology. Philadelphia: Lippincott-Raven. ISBN 0-7817-4865-8. 
2. ^ ^{a b c d} Savarese, Diane MF; Lynnette K Nieman (August 8, 2006). Clinical presentation and evaluation of adrenocortical tumors. UpToDate Online v. 15.1. UpToDate. Retrieved on June 5, 2007.
3. ^ ^{a b} Richard Cote, Saul Suster, Lawrence Weiss, Noel Weidner (Editor). Modern Surgical Pathology (2 Volume Set). London: W B Saunders. ISBN 0-7216-7253-1. 
4. ^ Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL. Harrison's Principles of Internal Medicine. New York: McGraw-Hill, 2005. ISBN 0-07-139140-1
5. ^ Laurence L. Brunton, editor-in-chief; John S. Lazo and Keith L. Parker, Associate Editors (2006). Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition. United States of America: The McGraw-Hill Companies, Inc.. ISBN 0-07-142280-3. 
6. ^ ^{a b} Allolio B, Fassnacht M (2006). "Clinical review: Adrenocortical carcinoma: clinical update.". J Clin Endocrinol Metab 91 (6): 2027-37. PMID 16551738.  Free Full Text.

External links

• Adrenocortical Support Group
• www.endotext.org article

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