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Adrenocortical Tumors: Recent Advances in Basic Concepts and Clinical Management
- Moderator: Stefan R. Bornstein, MD;
- Discussants: Constantine A. Stratakis, MD; and
- George P. Chrousos, MD
Abstract
Adrenocortical masses are among the most common tumors in humans. However, only a small proportion of these tumors cause endocrine diseases (such as primary hyperaldosteronism, hypercortisolism, hyperandrogenism, or hyperestrogenism), and less than 1% are malignant. In recent years, several of the molecular and cellular mechanisms involved in adrenal tumorigenesis have been unraveled. As a result, alterations in intercellular communication, local production of growth factors and cytokines, and aberrant expression of ectopic receptors on adrenal tumor cells have been implicated in adrenal cell growth, hyperplasia, tumor formation, and autonomous hormone production. Genetic and chromosomal abnormalities, including several chromosomal loci and the genes coding for p53, p57, and insulin-like growth factor II, have been reported in adrenal tumors. In addition, chromosomal markers have been identified in several familial syndromes associated with adrenal tumors; these include menin, which is responsible for multiple endocrine neoplasia type I, and the hybrid gene that causes glucocorticoid-remediable hyperaldosteronism. Algorithms for endocrine testing and imaging procedures are now available to codify screening for, confirmation of, and differentiation of causes of primary hyperaldosteronism and the Cushing syndrome. Improved radiologic, computerized radiologic, and magnetic resonance imaging techniques, as well as selective catheterization studies, are useful in localizing adrenal tumors and in distinguishing between benign and malignant lesions and between functional and nonfunctional nodules. Finally, recent refinements in the field of minimally invasive general surgery have made laparoscopic adrenalectomy the method of choice for removing adrenal tumors; this type of surgery allows shorter hospital stays, lower morbidity rates, and faster recovery.
Dr. Stefan Bornstein (Developmental Endocrinology Branch, National Institute of Child Health and Human Development [NICHD], National Institutes of Health [NIH], Bethesda, Maryland): Adrenocortical masses are common. On the basis of previous large autopsy series and the more recent use of sensitive computerized imaging techniques, it has been estimated that more than 3 of every 100 persons older than 50 years of age have adrenal nodules (1-5). Most of these nodules are benign and nonhypersecretory. Therefore, clinicians are routinely confronted with incidentally discovered adrenal masses and should be aware of recent developments in their biology and management.
Basic molecular and cell biology findings, including clarification of the roles of cell-cell communication, growth factors, cytokines, and aberrant cell membrane receptor expression, and other gene-related discoveries have increased our understanding of adrenal tumor biology. Here, we report on new aspects of adrenocortical tumorigenesis and their clinical implications. We also summarize recent advances in the diagnosis and management of adrenocortical tumors.
Intercellular Communication in the Adrenal Gland
Fundamental principles of molecular and cell biology have been unraveled from intensive studies of isolated primary cells or cell lines. To understand the functioning of any organ or gland in vivo, however, we must combine this knowledge with insights into the complex intercellular tissue interactions, including paracrine interactions.
The adrenal cortex and the medulla have traditionally been considered distinct organs, with cortical cells regulated primarily by the systemic hormones corticotropin and angiotensin II and with adrenomedullary cells regulated by preganglionic sympathetic neurons secreting acetylcholine (6, 7). However, several aspects of adrenocortical function cannot be explained so simply. In fact, discrepancies between concentrations of these regulatory hormones and secretory levels of corticosteroids strongly suggest the involvement of other regulatory mechanisms (8-10).
In addition to involving corticotropin and angiotensin II, the integrated control of adrenocortical function involves direct innervation (11, 12), regulation of blood supply to the gland (13), and intraglandular cell-cell interactions (8) (Figure 1). These systems not only are involved in the regulation of moment-to-moment functions but also participate in the development and differentiation of the adrenal gland and in adrenocortical adaptations and tumorigenesis (8, 9, 14).
Adrenomedullary chromaffin cells are found in all zones of the adult adrenal cortex. Some appear as rays, at times stretching from the adrenal medulla through the entire cortex (15, 16); others appear as islets of many cells or as single cells surrounded by steroid-producing cells. Medullary cells, especially in the zona glomerulosa, frequently spread into the subcapsular region, forming large nests of chromaffin cells (17, 18). But cortical cells are also located in the adrenal medulla. This intimate intermingling of the adrenal gland's two distinct endocrine cell types allows extensive contact areas for juxta and paracrine interactions (Figure 1 A). Chromaffin cells produce a wide variety of autocrine/paracrine regulatory factors, including neuropeptides, classic neurotransmitters, and cytokines that stimulate adrenocortical steroidogenesis (8, 19). In addition, a local corticotropin-releasing hormone (CRH)-corticotropin system in the adrenal medulla participates in the intra-adrenal regulation of steroidogenesis (8).
Although corticotropin and angiotensin II, the classic stimulants of the adrenal cortex, have specific direct effects on adrenocortical growth and differentiation, some of their actions seem to be indirectly mediated by locally produced regulators. Thus, various peptide growth factors, including basic fibroblast growth factor (20), insulin-like growth factors I and II (21), and transforming growth factor-β1 (22), have recently emerged as multifunctional molecules that typically play regulatory roles in several tissues, including the adrenal gland (23, 24). Their actions on mitogenesis and tissue growth are mediated through receptors with tyrosine kinase activity. These receptors activate proto-oncogene transcription factors, such as c-fos and c-jun, through the mitogen-activated protein-kinase pathway (25-28). The localized expression, release, and activation of such factors may moderate the actions of the circulating trophic hormones on the growth and differentiation of the zones of the adrenal cortex (23, 24).
Cytokines produced by immune cells that normally reside in the adrenal gland or by steroid-secreting cells directly influence adrenocortical function (29, 30). They may, like interleukin-1 and interleukin-6, stimulate steroidogenesis (31-33), or they may, like tumor necrosis factor-α or interferon-γ, exert a negative regulatory influence on adrenal function and growth (34, 35). Of note, adrenocortical cells of the inner cortical zone express MHC class II molecules (36, 37). Expression of MHC class II antigen appears with the maturation of complete adrenal zonation during adrenarche and is highly correlated with the cellular differentiation of the adrenal cortex (37). The expression of these molecules is increased in benign adrenal adenomas and is abrogated in adrenocortical carcinomas (38).
Intercellular Communication in Adrenocortical Tumors
The intercellular communication mechanisms described above are also involved in adrenal tumorigenesis. Hormonally active adrenocortical carcinomas abundantly express the insulin-like growth factor II gene, suggesting that insulin-like growth factor II may participate in the pathogenesis of these tumors (24, 39, 40). In addition, levels of both transforming growth factor-α and epidermal growth factor receptor expression were markedly higher in adrenocortical carcinomas than in benign tumors (41).
Adrenal adenomas frequently arise from cortical islets in the medulla (Figure 2 A). These islets, which are directly influenced by the surrounding adrenomedullary tissue, seem to be at greater risk for pathologic growth than the cortical cells within the adrenal cortex are (42).
Recent evidence shows that some adrenal tumors are triggered or promoted by aberrant expression and pathologic activation of several G-protein coupled receptors, such as those of vasopressin (43), gastric-inhibitory peptide (44, 45), vasoactive intestinal polypeptide (46), luteinizing hormone (47), and catecholamines (48). Therefore, the excess of cortisol production that causes the Cushing syndrome may in fact be under the control of inappropriate, illicit, or ectopic hormone receptors (49).
Recently, we reported on a patient who had a corticotropin-independent monoclonal adrenal adenoma with an aberrant expression of interleukin-1 receptor (50). Tumor cells produced cortisol in response to interleukin-1 but not in response to corticotropin. The adrenal tissue showed marked infiltration by mononuclear cells, which are a major source of cytokines, such as interleukin-1. In addition, monocytes stimulate production of cortisol by cultured human adrenocortical cells (51). Of note, lymphocytic infiltration was previously noted in histologic sections of as many as 15% of patients with the Cushing syndrome who had diffuse or nodular adrenal hyperplasia (Figure 2 B) (52, 53). It is not known whether these lymphocytes contribute to the hormonal excess or are a consequence of the adrenal disease.
In conclusion, aberrant hypersecretion of neuropeptides, neurotransmitters, growth factors, and cytokines that normally participate in the paracrine regulation of the adrenal cortex, together with ectopically or eutopically expressed receptors, may constitute an unregulated trophic stimulus that leads to increased function, hyperplasia, and tumorigenesis.
Molecular Genetics of Adrenocortical Tumors
Dr. Constantine A. Stratakis (Unit on Genetics of Endocrinology, Developmental Endocrinology Branch, NICHD, NIH): The genetic background of adrenocortical tumors remains poorly understood (1). Adrenocortical hyperplasia seems to be a polyclonal process; however, most adrenocortical tumors, whether benign or malignant, are monoclonal lesions (1), indicating that genetic changes at specific loci in the genome are needed for adrenal tumorigenesis. These genes and loci are listed in the Table.
For cortisol-producing tumors, the corticotropin receptor (the MC2R gene) (54, 55) and its signaling pathway, including the guanine-nucleotide-binding protein subunits Gsα (56) and Giα2 (G proteins), have been analyzed (57). For aldosterone-producing tumors, the aldosterone synthase receptor (the CYP11B2 gene) (58, 59) and the angiotensin II type 1 receptor (ATR-1) (60) have been investigated. Although no oncogenic mutations of the MC2R gene were found in adrenocortical tumors with variable histologic characteristics (55), the loss of heterozygosity of the MC2R gene locus on the short arm of chromosome 18 (18p11.2) occurred frequently in adrenocortical carcinomas but not in adenomas, supporting the involvement of this loss in carcinogenesis (54). Similarly, although the Gsα gene (the Gsp gene) was not mutated in sporadic adrenal tumors (56), patients with the McCune-Albright syndrome, who bear somatic mutations of this gene, may have such tumors (61).
In aldosterone-producing tumors, a hybrid gene created by the fusion of the corticotropin-regulated promoter of 11-β-hydroxylase (the CYP11B1 gene) and the sequence that codes for aldosterone synthase (the CYP11B2 gene) is the cause of familial hyperaldosteronism type I or glucocorticoid-remediable hyperaldosteronism (62), a disorder associated with aldosterone-producing tumors (63). However, the hybrid CYP11B1/CYP11B2 gene has not been found in other sporadic or familial aldosterone-producing adenomas (64), and the CYP11B2 gene chromosomal locus (8q24) (65) has been excluded in familial hyperaldosteronism type II (66), which also predisposes to aldosterone-producing adenomas (67). These investigations showed that the most obvious candidate genes did not participate in tumorigenesis in most adrenocortical lesions.
Molecular cytogenetic cloning approaches have been successfully used to investigate the genetics of adrenocortical tumors. Several chromosomal abnormalities have been implicated (68-71). Loss of heterozygosity and other studies of these loci led to the identification of genes with tumor suppression or oncogenic function in the adrenal cortex. These include the genes coding for the p53 (TP53) (on 17p13.1) (72, 73), p57 (KIP2) (on 11p15) (74, 75), and insulin-like growth factor II (on 11p15.5) (39, 40, 76) proteins. Of note, patients with the Beckwith-Wiedemann syndrome, which maps to 11p15, often develop adrenocortical cancer (77).
Loss of heterozygosity of the chromosome 17 locus of the gene that codes for p53 in tumors from patients with the Li-Fraumeni syndrome led to the identification of germline p53 mutations in this genetic condition (72). However, patients with the Li-Fraumeni syndrome rarely develop adrenal cancer (78). In sporadic adrenal tumors, somatic p53 mutations occur in approximately 30% to 50% of malignant lesions (1, 79, 80). Although p53 expression does not correlate well with prognosis, it is rarely seen in the earlier stages of tumorigenesis, indicating that p53 mutations develop late in the process (71, 81, 82). Thus, other genetic events precede and may even predispose to p53 mutations in adrenocortical tumors.
Comparative genomic hybridization is a molecular cytogenetic technique that allows genome-wide screening of tumor DNA to identify chromosomal gains and losses (83). Regions of gain may contain dominantly acting oncogenes, whereas tumor suppressor genes may map to deleted regions (84). Recently, this technique was used successfully to identify chromosomal alterations in adrenocortical tumors (82, 85), leading to the finding of chromosomal band 9q34 amplification in a subset of these tumors (82). Of note, overall chromosomal gains were far more common than losses in all adrenocortical tumors studied so far (57, 82, 85).
With the help of a genome-wide screen linkage analysis, we recently identified two genomic loci involved in benign primary pigmented nodular adrenocortical disease (61, 86, 87). This disorder, which is inherited in an autosomal dominant manner and is usually seen in association with the Carney complex (a multiple endocrine neoplasia [MEN] and lentiginosis syndrome [70]), has been mapped to genomic loci on chromosomes 2 (2p16) (86) and 17 (17q23-24) (87). Similarly, a genome-wide screen is ongoing to identify the gene or genes involved in the aldosterone-producing hyperplasia and adenomas associated with familial hyperaldosteronism type II (65-67, 88).
Menin, the gene responsible for MEN type 1 (89), is an example of a gene that may play a role in adrenocortical tumor formation and was identified by positional cloning (89). Approximately one third of patients with MEN type 1 have unilateral or bilateral adrenocortical tumors, although these lesions are clinically silent (90). Menin functions as a tumor suppressor gene (89), and loss of heterozygosity of its locus has been shown in adrenocortical tumors (69, 91).
In summary, genetic cloning approaches combined with loss of heterozygosity and tumor expression studies provide promising avenues for the improvement of our understanding of adrenocortical tumorigenesis.
Recent Advances in Diagnostic and Therapeutic Strategies
Dr. George P. Chrousos (Developmental Endocrinology Branch, NICHD, NIH): In adults, adrenal masses other than adrenocortical tumors are pheochromocytomas, ganglioneuromas, cysts, myelolipomas, adenolipomas, and metastases from other tumors. This overview focuses on adrenocortical tumors, which represent more than 80% of all adrenal masses (1). Primary adrenocortical tumors are classified as benign or malignant. A sharp distinction between accessory cortical nodules, focal hyperplasia, and true adenomas cannot always be made (5). Most of these masses are benign, nonhyperfunctional nodules that produce no clinical endocrine symptoms (92). They occur often, as has been shown in autopsy and cross-sectional studies done by using imaging studies in various countries (1, 3-5, 93-98). These “incidentalomas” gradually increase in frequency with age and occur in 3% to 7% of adults older than 50 years of age (5). About 5% to 8% of adrenal tumors are steroid-producing adenomas that cause hyperaldosteronism (the Conn syndrome) or primary hypercortisolism (the Cushing syndrome) (1). Aldosterone-producing adenomas are an uncommon cause of curable hypertension and are found in 0.7% to 2.2% of hypertensive persons (64, 99). Cortisol-producing neoplasms are responsible for 15% to 20% of cases of the Cushing syndrome; the rest are caused by corticotropin-secreting pituitary or ectopic tumors. Adrenocortical carcinomas are rare but exceedingly malignant. They account for 0.05% to 0.2% of all cases of cancer and have an annual incidence of approximately 1.7 new cases per million (100).
Clinical Presentation and Endocrine Testing
Aldosterone-Producing Adenomas
Aldosterone-producing adenomas are usually associated with hypertension with or without hypokalemia (101-103). Screening tests for an aldosterone-producing adenoma include evaluation of hypertension and measurement of serum potassium. The coexistence of hypertension and hypokalemia predicts primary aldosteronism in 50% of cases (104). Endocrine testing includes measurement of plasma aldosterone, plasma renin activity, and 24-hour urinary aldosterone excretion. With modern two-site immunoradiometric assays, the results of direct renin measurement seem to be as valuable and accurate as plasma renin activity (105). A ratio of plasma aldosterone to plasma renin activity of 20 or more (measured while the patient is upright) suggests the presence of an aldosterone-producing tumor (64). The principle behind this test is that as aldosterone secretion increases, plasma renin activity should decrease because of sodium retention.
Earlier reliance on plasma potassium screening (106) may have led to under-recognition of the role of primary hyperaldosteronism in hypertension. An early study (99) that used saline infusion as a screening test found primary hyperaldosteronism in 2.2% of 1036 unselected hypertensive patients. However, a smaller study (107) that used the ratio of plasma aldosterone to plasma renin activity suggested that the incidence of primary hyperaldosteronism may account for about 10% in the “essential hypertensive” population. Primary hyperaldosteronism is most often diagnosed in middle-aged adults (mean age at diagnosis, 42 years); in a study of 136 patients (108), it seemed to be more common in women (64%) than in men (36%).
Drugs and renal impairment both interfere with the diagnostic reliability of the aldosterone-to-renin ratio test. β-adrenoceptor blocking drugs and dihydropyridine calcium-channel blocking agents should be withheld for 2 weeks before testing. Spironolactone and loop diuretics induce secondary hyperaldosteronism and thus should be withheld for 6 weeks before testing (109). Diltiazem, a nondihydropyridine calcium-channel blocker, can be used to control blood pressure during testing for primary hyperaldosteronism (64).
After a positive result is obtained on screening, testing should confirm aldosterone secretory autonomy and determine whether the patient has an aldosterone-producing adenoma, which can be treated surgically or medically, or idiopathic hyperaldosteronism, which calls for medical treatment (Figure 3).
Traditionally, autonomous aldosterone secretion has been confirmed with the saline infusion test. Alternative tests include 24-hour urine aldosterone excretion during oral salt loading and the fludrocortisone suppression test (109, 110). The principle of all of these tests is that lack of suppression of aldosterone excretion with intravascular volume expansion indicates autonomous aldosterone production. The risks for fluid expansion and hypokalemia in susceptible patients should be considered.
An aldosterone-to-renin ratio greater than 20, a plasma aldosterone level greater than 277.4 pmol/L after the saline infusion test, or a urinary aldosterone excretion value greater than 27.7 to 38.8 nmol/d after oral salt loading confirms the diagnosis of primary hyperaldosteronism (64, 99) (Figure 3). To differentiate between an aldosterone-producing adenoma and other forms of primary hyperaldosteronism, postural testing is done after overnight recumbency and plasma aldosterone and renin activity are measured in the morning at baseline and after 2 hours of ambulation. In idiopathic hyperaldosteronism, an increase in aldosterone levels is most often seen, but patients with aldosterone-producing adenomas usually show a decrease in aldosterone levels. A diagnostic accuracy of 85% has been reported for postural testing (111). Levels of 18-hydroxycorticosterone are elevated (>2.76 nmol/L) in patients with aldosterone-producing adenomas and are lower in patients with idiopathic hyperaldosteronism (Figure 3).
Glucocorticoid-remediable aldosteronism can be diagnosed with a 4-day dexamethasone suppression test (0.5 mg orally every 6 hours). Compared with direct genetic testing, this test has a sensitivity of 92% and a specificity of 100% for the diagnosis of glucocorticoid-remediable aldosteronism (58). Today, the hybrid gene mutation that causes glucocorticoid-remediable aldosteronism can be identified in most patients by Southern blotting or by use of a long polymerase chain reaction technique (58, 112).
Cortisol-Producing Adenomas
For cortisol-producing adenomas, several laboratory studies are useful in establishing or confirming excessive glucocorticoid secretion and in monitoring patients (1, 113). A good screening study is the single-dose (1 mg) overnight dexamethasone suppression test (Figure 4). Hypercortisolism, however, is best established by measuring 24-hour excretion of urinary free cortisol (113, 115-117). More than 90% of patients with the Cushing syndrome have values for 24-hour excretion of urinary free cortisol greater than 551.8 nmol/d (normal range, 55.2 to 275.9 nmol/d) (115, 118). To confirm the diagnosis of the Cushing syndrome and exclude the possibility of a pseudo-Cushing state, the combined CRH-dexamethasone suppression test is highly reliable, with both sensitivity and specificity at almost 100% (113). This test is based on the principle that in the pseudo-Cushing states, excess cortisol is suppressible by dexamethasone and pituitary responsiveness to CRH is blunted. This is not the case in Cushing disease.
A low plasma corticotropin level associated with elevated concurrent plasma cortisol concentrations indicates autonomous activity of the adrenal glands (113, 118). Several dynamic endocrine tests differentiate adrenal Cushing syndrome from the corticotropin-dependent forms of the condition (113, 118). These tests include the classic high-dose dexamethasone suppression test and the ovine CRH stimulation test [114, 119-121], both of which are typically associated with 1) cortisol secretion's lack of responsiveness to dexamethasone and CRH in primary adrenal Cushing syndrome or the ectopic corticotropin syndrome and 2) low or undetectable plasma corticotropin levels in primary adrenal Cushing syndrome. Differentiating among corticotropin-dependent forms of the Cushing syndrome may require bilateral inferior petrosal sinus sampling for measurement of central to peripheral corticotropin-concentration gradients (114).
Adrenal Cancer
Most types of adrenal cancer are large, hormonally active tumors that produce excessive amounts of cortisol or adrenal androgens (1, 122), including dehydroepiandrosterone and its sulfate. Generally, adrenocortical carcinomas have several defective steroid biosynthesis enzymes, causing elevated levels of steroid precursors typical of enzymatic blocks (116). Feminization or hyperaldosteronism can be confirmed by elevated plasma estradiol or estrone levels and by measurement of aldosterone, 11-deoxycorticosterone, or corticosterone.
Adrenal Incidentalomas
Management of incidentally discovered adrenal masses is controversial, and a wide range of recommendations exists about which tests are necessary and which patients should have surgery (2-5, 95, 98). On the basis of our own experience and a consideration of recent multicenter studies (93-98), we suggest the following diagnostic approach: If an adrenal mass larger than 1 cm in diameter is found on imaging in an asymptomatic patient, biochemical screening should be done for latent hormonal hypersecretion syndromes, including hyperaldosteronism, hypercortisolism, pheochromocytoma, hyperandrogenism, and hyperestrogenism (3, 123). To screen for any aldosterone-producing adenoma, serum potassium levels should also be measured. For cortisol-secreting tumors, a single-dose (1 mg) overnight dexamethasone suppression test may be done. Given these findings and the clinical picture, further diagnostic steps should follow the algorithm for aldosterone-producing adenoma or the Cushing syndrome (Figure 3 and Figure 4). Elevated dehydroepiandrostenedione sulfate levels can be seen in patients with adrenal carcinomas and are useful for screening (1). The characteristic clinical symptoms of pheochromocytoma, including episodic headaches, sweating, and palpitations, may be absent. The potentially life-threatening course of undetected pheochromocytomas justifies screening by measuring plasma metanephrine levels or obtaining a 24-hour urine collection for catecholamines (124).
Imaging Procedures
Diagnosis of adrenal neoplasms depends on the identification of an adrenal mass on computed tomography (CT) or magnetic resonance imaging (MRI). Both normal and abnormal adrenal glands are readily visible on CT because of the surrounding adipose tissue in the retroperitoneum (125). Computed tomography provides information about size, homogeneity, presence of calcifications, areas of necrosis, and extent of local invasion, making it helpful in decisions about the potential malignancy and resectability of the neoplasm. Adrenal masses as small as 10 mm can be reliably detected by CT (126, 127), although the relative lack of retroperitoneal fat in children might decrease the sensitivity of the test in this population (128).
Adrenal CT is 70% to 80% sensitive in detecting aldosterone-producing adenomas. In one large series (111), mean tumor size was 1.8 cm, but 20% of these tumors were smaller than 1 cm. Adrenal incidentalomas are also common in older adults; thus, adrenal CT is considered adjunctive and is usually not used to direct adrenalectomy without other confirmatory data.
Whether MRI will prove superior to CT in diagnosing and differentiating among adrenal masses remains to be seen. Magnetic resonance imaging can show the invasion of an adrenocortical carcinoma into blood vessels, particularly the inferior vena cava and the adrenal and renal veins, in which tumor thrombi may occasionally be identified (125). It can also distinguish fairly accurately among primary malignant adrenocortical tumors, nonfunctioning adenomas, and pheochromocytomas by comparing the ratio of the signal intensity of each type of adrenal mass to that of the liver (128). Primary malignant adrenocortical lesions have intermediate-to-high signal intensity on T2-weighted images, nonfunctional adenomas have low signal intensity, and pheochromocytomas have extremely high signal intensity. In-phase out-of-phase MRI is emerging as a reliable method for distinguishing between adrenal incidentalomas and metastases (68, 129, 130) and proved useful in identifying an aldosterone-producing adenoma in a patient with hyperaldosteronism and bilateral nodules (125) (Figure 5). Other imaging methods, such as iodocholesterol scanning, venography, and arteriography, are rarely indicated (115, 128, 131), but recent data show that selenocholesterol scanning may prove useful in assessing malignancy (95).
Adrenal venous sampling remains the gold standard for the differential diagnosis of primary aldosteronism, especially because it has recently become clear that many tests used in the subtype evaluation of this condition provide variable and often inconclusive results (132). Comparison of aldosterone-to-cortisol ratios in the adrenal veins and the inferior vena cava allows detection of unilateral or bilateral sources of aldosterone hypersecretion. Although the cut-off for lateralization is controversial, ratios of 5:1 and 10:1 have been advocated (132, 133).
Management
Hormone-secreting adrenocortical tumors and hormonally silent adrenal masses 5 cm or more in diameter should be excised, as should smaller masses with a suspicious appearance on imaging (5, 115, 134).
Recent refinements in the field of minimally invasive general surgery have made laparoscopic adrenalectomy the preferred treatment for benign adrenal abnormalities (135-137). The advantage of this approach is that it allows precise dissection of the gland with minimal trauma. Patients benefit from shorter hospital stays, lower morbidity rates, and faster recovery (135, 136). Both transperitoneal and retroperitoneal approaches are possible (135), but the latter are preferred (138, 139). Tumors suspected of being malignant should be treated with conventional transperitoneal surgery (137, 139, 140).
All patients with aldosterone-producing adrenal tumors must have their blood pressure controlled and their potassium levels monitored before surgery. Unilateral adrenalectomy of an aldosterone-producing adenoma results in normotension in approximately 70% of cases and improves control of blood pressure and restores normal potassium levels in most cases (64, 103).
Persistent hypertension despite control of hyperaldosteronism may be due to coexisting essential hypertension, the long-term secondary vascular effects of hyperaldosteronism, or, rarely, another cause of secondary hypertension.
In patients with idiopathic hyperaldosteronism, hypokalemia and hypertension can be controlled with spironolactone (100 to 400 mg/d) or amiloride (5 to 30 mg/d), but additional antihypertensive agents are often needed (102). Hypertension in glucocorticoid-remediable aldosteronism can be controlled with physiologic doses of dexamethasone (64).
The treatment of choice for benign cortisol-producing adenomas is laparoscopic adrenalectomy (141). However, characterization of the pathophysiology of adrenal hyperplasias or tumors may eventually lead to the use of diverse pharmacologic therapies as alternatives (49). The success of pharmacotherapy has been illustrated by the short-term improvement in hypercortisolism seen with octreotide in patients with gastric-inhibitory peptide-dependent Cushing syndrome (44, 45) and by the long-term control of β-adrenergic receptor-dependent Cushing syndrome with propranolol (48).
For adrenocortical carcinoma, surgical resection is the only therapy that unquestionably cures or significantly prolongs survival, particularly if the disease is detected at stage I or stage II (132, 142). Radical excision with en bloc resection of any local invasion offers the best chance for cure or long-term survival. A wide exposure, achieved by using an extended subcostal incision or a thoracoabdominal approach, is needed (131). Patients who seem to have been cured with surgery still require long-term follow-up.
Mitotane has been used extensively in patients with adrenocortical carcinoma, but it is generally ineffective in prolonging overall survival in the advanced stages of the disease (122, 134). The side effects of mitotane are largely dose related. Weakness, somnolence, confusion, lethargy, and headache were reported in half of the patients treated (115, 122). More serious neurotoxicity, such as ataxia and dysarthria, may also occur (131). Most patients have gastrointestinal side effects, including anorexia, nausea, and diarrhea. Recently, monitoring serum mitotane concentrations was suggested as a way to provide long-term treatment with fewer side effects (143).
Incidentally discovered adrenal tumors should be surgically excised when hormonally active, regardless of their size (1). In addition, all nonsecretory tumors 5 cm or larger should be removed because the likelihood of malignancy increases with size (123). For patients with nonsecretory tumors smaller than 5 cm and no signs suggesting malignancy, an observational approach should include follow-up with CT 3 months after diagnosis (123).
Perspectives
Although the exact sequence of events leading to adrenal tumorigenesis is unclear, the process has multiple steps and varies from case to case. Many genetic abnormalities can account for the phenotypic heterogeneity and behavior of adrenocortical tumors. Production of local growth factors, cytokines, and neuroendocrine factors contribute to adrenal tumorigenesis, and aberrant expression of ectopic receptors allows control of adrenocortical cells by trophic factors not normally involved in their physiology.
Our increased understanding of the molecular and cellular mechanisms of adrenocortical oncogenesis may provide better choices and administration schedules for therapeutic agents. New compounds that capitalize on the differences in cell cycle control between normal cells and cancer cells are likely to be developed to maximize therapeutic effectiveness and minimize side effects. Finally, novel and improved imaging and minimally traumatic surgical techniques, such as laparoscopy, are bound to improve the treatment of adrenal disease.
Article and Author Information
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An edited summary of a Clinical Staff Conference held on 28 April 1998 at the National Institutes of Health, Bethesda, Maryland.
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Authors who wish to cite a section of the conference and specifically indicate its author may use this example for the form of the reference: Stratakis CA. Molecular genetics of adrenocortical tumors, pp 761-764. In: Bornstein SR, moderator. Adrenocortical tumors: recent advances in basic concepts and clinical management. Ann Intern Med. 1999; 130:759-771.
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Acknowledgments: The authors thank John Doppman, Monika Ehrhart-Bornstein, Holger Willenberg, and David Torpy for constructive advice and support.
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Grant Support: By grants from the Mildred Scheel Stiftung (10-1070-Re I) and by a Heisenberg grant (DFG BO 1141/6-1) (Dr. Bornstein).
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Requests for Reprints: Stefan R. Bornstein, MD, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N 262, 10 Center Drive, MSC 1862, Bethesda, MD 20892-1862; e-mail bornstes{at}ccl.nichd.nih.gov.
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Current Author Addresses: Dr. Bornstein: Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N 262, 10 Center Drive, MSC 1862, Bethesda, MD 20892-1862.
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Dr. Chrousos: Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N 262, 10 Center Drive, MSC 1862, Bethesda, MD 20892-1862.
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Dr. Stratakis: Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N 262, 10 Center Drive, MSC 1862, Bethesda, MD 20892-1862.
- Copyright ©2004 by the American College of Physicians
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