LabMed

Adrenocortical Carcinoma (ACC)

At a Glance

Adrenocortical carcinomas (ACCs) are rare (1-2 per million population), aggressive tumors that may be functional (hormone secretory) and cause Cushing's syndrome and/or virilization and present as an abdominal mass or incidental findings. ACCs can develop at any age, and there is a bimodal age distribution with disease peaks before 5 years of age and the fourth to fifth decade of life. Approximately 60% of ACC cases are secretory, and it is usually present with Cushing's syndrome (45%) alone. Twenty-five percent of these can be mixed in nature (both Cushing's syndrome and virilization) with overproduction of both glucocorticoids and androgens. Less than 10% of the secretory ACC cases can manifest as virilization alone. Most ACC cases are sporadic in nature, but some have been described as a component of severe hereditary cancer syndromes:

  • Li-Fraumeni syndrome

  • Beckwith-Wiedemann syndrome

  • Multiple endocrine neoplasia type 1 (MEN1)

  • SBLA syndrome

Most patients with nonfunctioning tumors present with clinical manifestations related to tumor growth (abdominal or flank pain), weight loss, fever, back pain, abdominal fullness, or symptoms related to metastases. Most are incidentally found adrenal masses detected on a radiographic image performed for different reasons.

Functional ACC clinical symptoms are associated with glucocorticoid excess: weight gain, weakness, and insomnia develop rapidly, hypertension, hypokalemia related to hyperaldosteronism, and hypoglycemia . Hirsutism, facial acne, oligo/amenorrhea, and increased libido are all possible presenting symptoms.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

A careful history and physical examination should be performed to exclude signs and symptoms of pheochromocytoma, hyperaldosteronism, and Cushing's syndrome.

The following tests are recommended:

  • fasting blood glucose

  • plasma potassium

  • cortisol

  • adrenocorticotropic hormone (ACTH) 24-hour urinary free cortisol (UFC)

  • low-dose dexamethasone test (DST)

  • adrenal androgens (DHEA, DHEA sulfate [DHEA-S], androstenedione, testosterone)

  • 17-hydroxyprogesterone

For hormone-secreting ACCs, the following tests are useful to determine the secretory activity of the tumors:

  • 24-hour Urinary Measurements of Free Cortisol (UFC)

  • Late-night Salivary Cortisol

  • 1 mg Overnight Dexamethasone Suppression Test (DST)

  • Longer Low Dose Dexamethasone Suppression Test (2 mg/day for 48 hours)

(For the details of these tests and interpretations, see chapter on Adrenal Adenoma.)

Measurements of adrenal androgens in serum and urine can be helpful in the differential diagnosis of some adrenal disorders in adrenal carcinoma.

Mechanism by which adrenal androgens DHEA, DHEA-S, and androstenedione are regulated is not known. These compounds are largely inactive, but, because they are precursors of adrenal androgens testosterone and dihydrotestosterone, they are referred to as adrenal androgens.

Tests Results indicative of the Disorder

DHEA and DHEA-S

DHEA has very low androgenic potency but serves as the major direct or indirect precursor for most sex steroids. DHEA is secreted by the adrenal gland, and production is, at least partly, controlled by ACTH. The bulk of DHEA is secreted as a 3-sulfoconjugate DHEA-S. Both hormones are albumin bound, but DHEA-S binding is much tighter. As a result, circulating concentrations of DHEA-S are much higher (>100-fold) compared to DHEA. In most clinical situations, DHEA and DHEA-S results can be used interchangeably. ACTH acutely stimulates the secretion of DHEA but not DHEA-S. Extremely high levels (>700 or 800 ug/dL) in women are suggestive of a hormone-secreting adrenal tumor. By contrast, DHEA-S04 levels are typically normal in the presence of ovarian tumors.

Androstenedione

Androstenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens (estrone and estradiol). It is a major adrenal androgen in serum; it is produced by testes, as well as ovaries. It is very useful in the diagnosis of virilism and hirsutism. High levels are found in ACCs.

Testosterone

Testosterone circulates in the blood of men and women in several forms. In healthy adults, approximately 44% of circulating testosterone is specifically bound to sex hormone–binding globulin (SHBG), 50% is nonspecifically bound to albumin, and 3-5% is bound to cortisol binding globulin, indicating only 2-3% is unbound and free. Current methods available to evaluate the androgen status include measurement of total testosterone, free testosterone by direct immunoassays, equilibrium dialysis, HPLC-MS, SHBG, calculated free (non–SHBG-nonalbumin bound) testosterone, and bioavailable (non–SHBG bound) testosterone. In most, but not all, clinical conditions, a measurement of total testosterone is adequate for the evaluation of a patient. It is widely believed that SHBG bound testosterone is not readily available to most tissues, whereas albumin bound and free testosterones are bioavailable.

Testosterone is increased in an adrenal virilizing tumor, causing premature puberty in boys or masculinization in women.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

DHEA and DHEA-S

DHEA levels increase until 20 years of age to a maximum roughly comparable to that observed at birth. Levels then decline during the next 40-60 years to about 20% of peak levels. Currently, the correlation of serum DHEA/DHEA-S level with disease risk factors has not been completely established. There are currently no established guidelines for DHEA replacement/supplementation therapy or its biochemical monitoring.

Testosterone

Due to the availability of many different forms of testosterone assays, as well as the confusion in the literature regarding their clinical relevance, a lack of consistency exists for its measurement in routine clinical situations. The earliest approaches to the measurement of free testosterone were equilibrium dialyses and ultrafiltration. These assays were very cumbersome for routine use.

Indirect measurement of free testosterone using isotope labeled testosterone was 1 of the earlier methods proposed and widely used. The Endocrine Society recently reported a review of the evidence that the analog-based free testosterone immunoassays should be avoided because of the problems with accuracy and sensitivity. Free testosterone measurements by calculation using algorithms based on the law of mass action, which requires total testosterone, SHBG, and albumin concentrations, have excellent correlations with physical separation measures.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

DHEA and DHEA-S

Many drugs and hormones can result in changes in DHEA-S levels. In most cases, the drug-induced changes are not large enough to cause diagnostic confusion, but, when interpreting mild abnormalities in DHEA-S levels, drug and hormone interactions should be taken into account. Examples of drugs/hormones that can reduce DHEA-S levels include insulin, oral contraceptive drugs, corticosteroids, central nervous system agents that induce hepatic enzymes (e.g., carbamazepine, clomipramine, imipramine, phenytoin), many antilipemic drugs (e.g., statins, cholestyramine), dopaminergic drugs (e.g., levodopa/dopamine, bromocryptine), fish oil, and vitamin E. Drugs that may increase DHEA-S levels include metformin, troglitazone, prolactin, danazol, calcium channel blockers (e.g., diltiazem, amlodipine), and nicotine.

Testosterone

Use of certain drugs that alter thyroxine-binding globulins (NSAIDs) may also affect testosterone-binding globulins; however, the free testosterone level will not be affected.

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