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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 84Neoplasms of the Adrenal Cortex

, MD.

Adrenal cortical carcinomas are rare, highly malignant tumors that account for only 0.2% of deaths due to cancer. Their incidence has been estimated at 2 per million people per year. About half of these tumors produce hormonal and metabolic syndromes that lead to their discovery. The other half are silent and are discovered with metastasis or when the primary tumor becomes large enough to produce abdominal symptoms. While adrenal cancer can occur at any age, most cases occur between ages 30 and 50 years.1

Pathogenesis

The etiology of adrenal cancer remains unknown. Cases of adrenal cancer have been described in families with a hereditary cancer syndrome, who exhibit mutations in tumor suppressor genes. One such condition is the Li-Fraumeni syndrome, characterized by sarcoma, breast cancer, brain tumors, lung cancer, laryngeal carcinoma, leukemia, and adrenal cortical carcinoma. The deleterious genotype in these cases has been expressed through several generations and found in both children and adults.2,3

Several theories have been put forth to explain tumor development in adrenal cortical carcinoma. They include chromosomal alterations leading to abnormal regulation of a gene product or chronic stimulation of the gland. There are data supporting the presence of changes in the p53 tumor suppressor gene located on chromosome 17p and its 53 kD protein.4–6 Some of these were point mutations in exons 5 through 8 and resulted in a single amino acid change, leading to synthesis of a protein with an altered half-life. A germline mutation of the p53 gene was found in a patient with an incidentally found adrenal cortical carcinoma.7 This mutation resulted in a premature stop codon. However, mutations at the p53 loci are not found only in malignant adrenal tumors; they have also been found in benign adrenal adenomas and pheochromocytomas.8 Another study9 showed alteration in the p53 gene product in about 50% of cases of adrenal cortical carcinoma but was unable to show that the p53 status had any effect on long-term survival.

Changes in the rb gene have also been reported but the nature of the changes in this gene and its regulation has not been completely worked out. As with the p53 gene, allelic loss at the rb gene locus on chromosome 13q has been described in adrenal cortical carcinoma.4 Other genetic markers examined have included the h19, the insulin-like growth factor-II (igf-II) and the p57kip2 genes. These genes have been mapped to chromosome 11p15.510 and appear to be important for fetal growth and development. The levels of expression of the h19 and igf-II genes are very high in human fetal adrenal glands,11 but they subsequently decrease by 50% in adults. The gene product for p57kip2, a member of the p21CIP1 cyclin-dependent kinase family, appears to regulate cell proliferation, exit from the cell cycle, and maintenance of differentiated cells. This gene product is usually found to be high in most normal human tissues. h19 and p57kip2 gene expression is Adrenocorticotropic hormone (ACTH) dependent and regulation of the p57kip2 gene appears to be related to the Cyclic Adenosine Mono Phosphate (cAMP)-dependent protein kinase pathway.10 Expression of the h19 gene is markedly reduced in both nonfunctioning and functioning adrenal cortical carcinomas, especially in tumors producing cortisol and aldosterone.10 There is also a loss of activity of the p57kip2 gene product in virilizing adenomas and adrenal cortical carcinomas,10 suggesting that this gene product plays a role in the normal maintenance of adrenal cortical differentiation and function. In contrast, igf-II gene expression has been shown to be high in adrenal cortical carcinomas. Finally, the c-myc gene has been evaluated for a possible role in adrenal tumorigenesis. c-myc gene expression is relatively high in neoplasms, and it is often linked to poor prognosis. However, in contrast to other neoplasms, adrenal cortical carcinomas have low expression of c-myc, approximately 10% of that found in normal adrenal tissue.12 The c-myc gene is generally expressed in normal adrenal glands and usually localized to the zona fasciculata and zona reticularis. The significance of a low c-myc gene expression in adrenal cancer is unknown.

Diagnosis

Cushing’s syndrome is the most common clinical presentation in adult patients with adrenal cancer. Characteristically, these patients describe rapid development (3–6 months) of the clinical manifestations of cortisol excess, including weight gain, muscle weakness, easy bruising, irritability, and insomnia. In addition, there commonly are manifestations of androgen excess, including hirsutism, acne, and irregular menses or amenorrhea in women. While virilization frequently accompanies Cushing’s syndrome, the predominant clinical manifestations may be those of androgen excess, with only subtle evidence of hypercortisolism. The androgen excess may decrease the severity of the catabolic effect of hypercortisolemia such that skin and muscle atrophy may not be as readily apparent as in those with benign tumors. Patients with metastatic disease complain of anorexia and weight loss rather than weight gain. Adrenal cortical carcinomas causing Cushing’s syndrome are large with an average weight of 800 g, but the clinical manifestations of hormone excess may lead to earlier diagnosis and the finding of smaller tumors.

Hormonal findings in patients with clinical manifestations of Cushing’s syndrome include high urinary free cortisol, serum cortisol and Dehydroepiandrosterone Sulfate (DHEA-S) at baseline and failure to suppress with a high (8 mg) dose of dexamethasone. ACTH levels are usually suppressed. The steroid profile in serum or urine can help distinguish between benign and malignant adrenal cortical tumors because of the presence of intermediary precursors in the steroid biosynthetic pathway or their metabolites in patients with malignant neoplasms (Fig. 84.1).

Figure 84.1. Pathways of steroid biosynthesis in the adrenal cortex.

Figure 84.1

Pathways of steroid biosynthesis in the adrenal cortex. Specific enzyme defects in adrenal cortical carcinoma lead to pathway blocks and production of steroid precursors. The numeral1represents 3β-hydroxysteroid dehydrogenase; 2 represents 21-hydroxylase (more...)

Sex hormone–producing carcinomas lead to virilization in women and manifestations of feminization in men. Women with virilizing adrenal cortical carcinomas present with marked androgen-type hirsutism, male-pattern baldness, deepening voice, breast atrophy, clitoral hypertrophy, decreased libido, and oligo- or amenorrhea. In contrast, manifestations of androgen excess are less noticeable in men. Prepubertal boys with androgen excess develop precocious puberty without concomitant testicular enlargement. Feminizing tumors in women cause breast tenderness and dysfunctional uterine bleeding. Estrogen-secreting tumors in men are associated with gynecomastia, breast tenderness, testicular atrophy, and decreased libido. Prepubertal girls with feminizing tumors experience early breast and uterine development and onset of menarche.

Patients with virilizing tumors demonstrate high serum levels of testosterone, androstenedione, and DHEA-S, while patients with feminizing tumors have high serum estradiol levels. Total testosterone levels in virilized women are greater than 2.0 ng/mL (normal 0.3–0.6 ng/mL).

Aldosterone-producing adrenal cortical carcinomas are extremely rare. They present with hypertension and hypokalemia, which are typical clinical manifestations of primary aldosteronism. Compared with patients with benign aldosterone-secreting adenomas, those with carcinoma have larger tumors, higher aldosterone levels, and more severe hypokalemia.13,14 Evaluation should include measurement of serum electrolytes, aldosterone, and plasma renin levels. Findings include severe hypokalemia with potassium levels below 2.5 mEq/L, hypernatremia, and metabolic alkalosis. Serum aldosterone levels are high, and plasma renin levels are suppressed.

Silent adrenal cortical carcinomas do not present with recognizable symptoms of excessive hormone production and are detected when they attain a large size and cause local symptoms. Some of these tumors, however, may be detected incidentally in the course of investigation of unrelated abdominal complaints. A hormonal profile should also be obtained on patients with apparently silent adrenal tumors. Some of these tumors produce biosynthetic steroid pathway intermediates, such as progesterone and 11-deoxycortisol.15 It is important to determine the level of these steroids prior to surgical resection of the tumor because these hormones can be used as biochemical markers in the postoperative follow-up.

Differential Diagnosis

A major dilemma in the differential diagnosis of adrenal cancer arises with incidentally discovered adrenal masses. These masses are found in 1 to 3% of computed tomographic (CT) scanning of the abdomen. Most of these masses are benign, and adrenal cortical adenomas are 60 times more common than primary carcinoma.16 When these adrenal masses are malignant, they frequently are metastatic from extra-adrenal neoplasms. Age, ethnic background, and comorbidities should be considered when evaluating an incidentally found adrenal mass. These masses are uncommon under the age of 30 years and their prevalence increase with age. Thus, an incidentally discovered adrenal mass in a young person is of greater concern and should be monitored more closely and for a longer period in order to rule out malignancy. Silent adrenal masses are more common among African Americans and in patients with diabetes mellitus, obesity, and hypertension.

The size of the mass is an important consideration in determining if it is benign or malignant. Masses less than 3 cm are usually benign;17 in contrast, the probability that the mass is malignant is greatly increased when they measure more than 6 cm. There is uncertainty with masses measuring 3 to 6 cm and concern that adrenal cortical carcinomas could be missed in early stages of development. Since early resection of these tumors offers the best chance for cure or long-term survival, an accurate diagnosis of a small tumor is very important. Nonfunctioning small adrenal masses less than 3 cm in diameter usually remain stable for many years. Malignant lesions, however, may be initially small but slowly enlarge over the subsequent years. In contrast, functioning adrenal tumors are associated with significant morbidity that depends on the metabolic effects of the hormones produced in excess.

Imaging Characterization of Adrenal Masses

A variety of imaging procedures can be useful in the localization and evaluation of the benign or malignant character of an adrenal cortical neoplasm and the extent of disease.

Computed Tomography

Unenhanced and contrast-enhanced CT have been used to distinguish benign from malignant adrenal masses.18,19 on the basis of their lipid content. Lipid-rich masses are usually benign, while lipid-poor masses are frequently malignant. Enhancement is measured in Hounsfield units (HU). Low attenuation lesions have low HU values. Using unenhanced CT, it was shown that adenomas have values less than +10 HU, while nonadenomas have values greater than +18 HU. These criteria give a sensitivity of 73% for distinguishing adenomas from nonadenomas and a specificity of 96%. CT images obtained 1 hour after the injection of contrast show an enhancement of 11± 13 HU (< 30) for adenomas and of 49 ± 8.3 HU (> 30) for nonadenomas, with a sensitivity of 95% and a specificity of 100 %. Adenomas also exhibit a > 50% washout within 15 minutes of contrast injection, while nonadenomas exhibit a greater retention of contrast. Malignant adrenal masses are generally larger than 5 cm, have an inhomogeneous pattern because of areas of necrosis within the tumor, and are frequently invasive of the upper pole of the adjoining kidney and of the inferior vena cavae (Fig. 84.2). The CT procedure also helps determine the presence of involved lymph nodes and hepatic or pulmonary metastases. A definition of metastatic involvement is important in determining the stage of the disease and treatment goals.

Figure 84.2. CT appearance of a right adrenal cortical carcinoma.

Figure 84.2

CT appearance of a right adrenal cortical carcinoma. The mass is inhomogeneous, secondary to areas of necrosis within the tumor.

Ultrasonography

Malignant lesions vary in echo texture and are heterogeneous in appearance, with focal or scattered echopenic or echogenic zones representing areas of tumor necrosis, hemorrhage, and/or calcification.18,20

Magnetic Resonance Imaging

Tumors appear as hypointense masses compared with the liver on T1-weighted images and hyperintense on T2-weighted images. MRI also demonstrates displacement or invasion of adjacent organs as well as liver metastases. Superior blood vessel identification and the multi-planar capabilities of MRI make it the imaging modality of choice in evaluating the extent of disease and planning surgical excision.21 The distinction between benign and malignant masses on the basis of the presence of lipid can also be determined by chemical shift MRI. Lipid-rich adenomas show a 34% change in relative signal intensity between in-phase and out-of-phase imaging, while nonadenomas do not change. This technique gives a specificity of 100% and a sensitivity of 81% in distinguishing these lesions.22

131I-6β-iodomethylnorcholesterol Scintigraphy

Most adrenal cortical carcinomas fail to image with this radionuclide. Since cortisol production suppresses ACTH secretion and the function of the contralateral adrenal gland, patients with cortisol-producing adrenal cortical carcinomas fail to show an image either at the site of the tumor or the contralateral gland. Aldosterone-, androgen- or estrogen-secreting tumors generally appear as an area of decreased uptake on the side of the tumor mass. The decreased or absent tracer uptake by adrenal cortical carcinomas is in contrast with the increased concentration of radionuclide by benign tumors.14 This distinction is not absolute. Patients with adrenal cortical carcinoma may occasionally exhibit positive nuclear scans. On the basis of these imaging characteristics, CT and iodocholesterol scintigraphy can be used together in the diagnosis of small (less than 4 cm) euadrenal masses. Concordant images (CT image and increased uptake on the same side) are benign in 100% of cases, while discordant images (a CT tumor image on one side and increased uptake on the contralateral side) are malignant in 73% of the cases.23

Staging

Adrenal cortical carcinoma can be staged on the basis of the size of the primary tumor and extent of regional or distant tumor involvement, according to the MacFarlane classification,24 as modified by Sullivan (Table 84.1).25 Patients in stage I have tumors that measure less than 5 cm in size and have no evidence of lymph node involvement or metastases; patients in stage II have tumors larger than 5 cm but are free of lymph node involvement or metastases. Patients in stage III exhibit tumors of any size with local lymph node invasion or have experienced local recurrence. Patients in stage IV have distant metastases. The sites of tumor spread in stage IV are summarized in Table 84.2. The most frequent sites for metastases are the lung, liver, lymph nodes, and bone. The stage at which an adrenal cortical carcinoma is defined determines the prognosis.26,27 While 50% of patients in stages I, II, or III are alive 40 months after diagnosis, only 10% of patients in stage IV are alive at that time.

Table 84.1. MacFarlane Classification of Adrenal Cortical Carcinoma Based on Size and Extent of Disease.

Table 84.1

MacFarlane Classification of Adrenal Cortical Carcinoma Based on Size and Extent of Disease.

Table 84.2. Sites of Metastasis in Stage IV Adrenal Cortical Carcinoma.

Table 84.2

Sites of Metastasis in Stage IV Adrenal Cortical Carcinoma.

Pathologic Diagnosis

Pathologic criteria, alone or in combination with clinical features, have been used in the differential diagnosis of benign and malignant adrenal cortical tumors and in assessing their prognosis.28 Adrenal adenomas are usually well encapsulated and homogeneous on cross-section (Fig. 84.3A) and do not metastasize; in contrast, adrenal carcinomas are large, multi-lobulated tumors with areas of necrosis and evidence of capsular and vascular invasion (Fig. 84.3B). Various systems of histologic diagnosis have been proposed for adrenal cortical carcinomas, but the most commonly used system is the one described by Weiss.29 Nine histologic findings have been described: (1) high nuclear grade, (2) mitotic grade greater than 5 per 50 high power fields (HPF), (3) atypical mitotic figures, (4) eosinophilic tumor cell cytoplasm, (5) diffuse architecture, (6) necrosis, (7) venous invasion, (8) sinusoidal invasion, and (9) capsular invasion. Malignant tumors meet four or more of these histologic criteria. The three most commonly found are a mitotic rate greater than 5 per 50 HPF, atypical mitotic figures, and venous invasion.

Figure 84.3. Comparison of gross anatomical appearance of benign adrenal adenomas and malignant adrenal cortical carcinomas: A.

Figure 84.3

Comparison of gross anatomical appearance of benign adrenal adenomas and malignant adrenal cortical carcinomas: A. 2.5-cm benign adrenal adenoma causing Cushing’s syndrome. The tumor is well encapsulated and of homogeneous appearance. B. 25-cm (more...)

The mitotic rate is an important criterion not only for distinguishing malignant from benign tumors but also for predicting the clinical virulence of adrenal cortical carcinomas. Patients with carcinomas with a high mitotic rate (more than 20 mitoses per 10 HPF) have a shorter disease-free survival period, as compared with those with low mitotic rates (less than 20 mitoses per 10 HPF).

Most adrenal cortical carcinomas are of large size, but size alone does not have any effect on survival time or has minimal effect. Depending on the degree of cell differentiation, adrenal cortical carcinomas have been classified as well differentiated or anaplastic. While better-differentiated carcinomas may have a less aggressive course than the anaplastic tumors, cell differentiation may not predict survival independently of the mitotic rate.

Attempts have been made to study adrenal cortical carcinomas by immunohistochemical analysis. In contrast to other malignant neoplasms, adrenal cortical carcinomas do not consistently express keratin, alpha-1 antitrypsin or alpha fetoprotein. Similarly, beta-2 microglobulin is rarely expressed by adrenal cancer. Studies of DNA ploidy have given inconsistent results and are not reliable indicators of histologic diagnosis or prognosis. Identification of specific gene mutations in adrenal cortical carcinomas may, in the future, be helpful in determining not only diagnosis but the malignant grade and prognosis of individual tumors.

Management of Adrenal Cortical Carcinoma

Therapeutic interventions used to treat patients with adrenal cancer include surgery, radiation therapy, cytotoxic chemotherapy, and mitotane.30

Surgical resection, even if incomplete, should be considered as the initial step in therapy. Because most adrenal carcinomas are large, the surgical approach should be either transabdominal or thoracoabdominal with an incision of sufficient length to allow adequate exploration and resection of contiguous organs, if necessary, to remove gross tumor. The surgical goal should be the resection of the entire tumor mass, whenever possible. Even if this is not possible because of local extension into other structures, tumor debulking should be carried out to the maximum degree possible. It is frequently necessary to remove the adjoining kidney en block with the tumor because of invasion of the upper pole. In cases of liver metastases, a partial lobectomy or segmentectomy, with resection of the involved portion of the liver, has led to long-term remission.31 These aggressive efforts to excise all grossly visible tumor are justified because chemotherapy appears to be most effective when the tumor burden is minimal.

Other approaches to treatment are radiation therapy and chemotherapy. Adrenal cortical carcinomas have been reported to be resistant to radiation therapy, which only causes transient reduction of local disease.32 However, these earlier reports were based on techniques and equipment much less powerful than those currently available. It is possible that better responses can be attained with higher doses, administered using conformal radiotherapy.

Chemotherapy has resulted in only temporary improvement. Chemotherapeutic agents used in the treatment of metastatic adrenal carcinoma include Adriamycin, cisplatin, etoposide, paclitaxel, 5-fluorouracil (5-FU), oncovin, cyclophosphamide, and suramin. The consensus from several series is that systemic chemotherapy is not very effective when given in stage IV; however, several factors contribute to the difficulty of comparing treatment outcomes. These include a relatively small number of patients per series, variability of treatment between and within series, lack of definition of the extent of disease at the time of treatment, and variable grades of malignancy. Some series include patients with low-grade malignancy as well as patients with high-grade malignancy. In addition, treatments are difficult to compare because there is lack of a uniform definition of response, the duration of response is not always clearly stated, patients within a series frequently receive multiple drugs in variable sequence, and radiation therapy is sometimes combined with chemotherapy.

Mitotane has been used consistently in the treatment of patients with metastatic adrenal cortical carcinoma, but there is not complete consensus regarding its efficacy.33,34 Mitotane is an adrenalytic drug with selective action on the adrenal cortex. When given to patients with pituitary ACTH-dependent adrenal cortical hyperfunction, mitotane induces suppression of cortisol secretion and selective chemical ablation of the fasciculata and reticularis zones of the adrenal cortex. Mitotane belongs to the class of drugs that require transformation into active metabolites for therapeutic action. The active metabolite may covalently combine with specific targets in the cells responsive to the drug, and/or induce oxygen activation leading to toxicity. There is evidence that mitotane is transformed to an acyl chloride by a mitochondrial P450-mediated hydroxylation and that the acyl chloride covalently combines with specific bionucleophiles within the adrenal cortical cell for the adrenalytic effect to take place. It is possible that adrenal tumors vary in their ability to effect metabolic transformation or initiate free-radical production, thereby expressing variable sensitivity to mitotane. In a series of reports,35 mitotane has been associated with partial or complete response in 33% of patients with adrenal cancer. The timing of initiation of chemotherapy may influence patient survival. It has been reported36,37 that adjuvant therapy with mitotane is associated with prolonged survival when initiated immediately after the primary tumor has been surgically excised and before local extension or additional metastases develop. However, prospective studies in which patients were randomly assigned to either adjuvant therapy with mitotane or no therapy failed to show a beneficial effect of mitotane in extending life expectancy.38

Mitotane causes significant toxicity in therapeutically effective doses. The adverse effects of mitotane are dose dependent and usually intolerable when doses exceed 6 g daily, a dose that may be required to achieve therapeutic blood levels of at least 14 μg/dL.39 Treatment begins with doses of 1 g twice daily, and the dose is gradually increased to tolerance. The drug is best administered with fat-containing foods, since its absorption and transport appear coupled to lipoproteins. The cortisol response to mitotane can be determined by measuring urinary free cortisol. Mitotane increases the binding of cortisol to corticosteroid-binding globulin (CBG), and serum cortisol levels can be elevated even when the circulating free cortisol level is not.40 Treatment with mitotane inhibits hormone production and eventually causes necrosis of the contralateral adrenal gland. Patients must receive cortisol replacement of 25 to 35 mg daily. Synthetic glucocorticoids, such as prednisone and dexamethasone, are less desirable because their metabolism may be enhanced by mitotane, making it difficult to determine the optimal replacement dose. In low doses (2–4 g daily), mitotane has less adrenalytic effects on the zona glomerulosa and is less likely to suppress aldosterone production. With larger doses, replacement with flurocortisol may be necessary.

Suramin, a drug known for its antiparasitic effects, may have some therapeutic efficacy as monotherapy in patients with metastatic adrenal cortical carcinoma.41 When given to patients with adrenal carcinoma, a partial to minor response was observed in some patients. A greater response was obtained when suramin and mitotane were combined.

Long-Term Treatment Outcome

Medical therapy for adrenal cortical carcinoma is of limited effectiveness.42,43 However, there are a significant number of patients whose life expectancy has been extended, with acceptable morbidity. Combined surgical and medical treatment appears to be more effective than medical treatment alone, especially for patients with localized or regional disease (stages I–III). In a comparison of 18 patients treated with mitotane alone and 15 treated with combined surgical resection and mitotane chemotherapy, those who underwent surgical treatment had a more favorable response, with 33% of patients surviving more than 5 years from the time of first recurrence.44 In a study of 49 patients with adrenal carcinoma, surgical excision offered the best chance for prolonged survival. Forty-three percent of patients with a completely resectable tumor were alive with no evidence of disease 7.3 years postoperatively.45 While comparing various types of therapy in 110 patients with adrenal cortical carcinoma, it was noted that 56% of patients responded to surgery for localized and regional disease with a disease-free survival time of at least 2 years. In contrast, abdominal radiation therapy was effective in 15%, systemic chemotherapy in 9%, and mitotane therapy in 29%.46 In a review of 82 patients, it was noted that survival of patients with metastatic disease was poor and not improved by treatment with mitotane, cytotoxic chemotherapy, or radiation therapy.47

Thus, survival of patients with adrenal carcinoma with recurrent or metastatic disease is better for those who can receive surgical treatment rather than medical treatment alone. With surgical treatment, 50% of patients survive an average of 70 months, while less than 10% of patients are alive for this length of time with medical treatment alone. The surgical treatment involves not only resection of the primary tumor but also repeated resection of metastases.

A management algorithm for each stage of the disease is provided in Fig. 84.4.

Figure 84.4. Algorithm summarizing the management strategy of adrenal cortical carcinoma based on stage of the disease.

Figure 84.4

Algorithm summarizing the management strategy of adrenal cortical carcinoma based on stage of the disease. Hormone measurements should be followed as tumor markers in patients with functioning adrenal cortical carcinoma.

The Use of Inhibitors of Adrenal Function in Patients with Functioning Adrenal Cortical Carcinoma

The metabolic changes associated with excessive hormonal production can cause significant morbidity and shortened life expectancy in patients with residual disease who do not respond to antitumor therapy. Inhibitors of adrenal function have been used to suppress steroid hormone production and improve the clinical manifestations of the disease. The most commonly used inhibitors are ketoconazole and aminoglutethimide.

Ketoconazole is an imidazole derivative that inhibits the synthesis of cortisol by inhibiting mitochondrial cytochrome P450-dependent enzymes, such as cholesterol side-chain cleavage and 11-beta-hydroxylase, in rat and mouse adrenal preparations. It is also an important inhibitor of gonadal and adrenal steroidogenesis in vivo, when given in doses as low as 200 to 600 mg/d. Ketoconazole has been used to treat patients with Cushing’s syndrome and virilization caused by adrenal carcinoma.48 Clinical improvement occurs frequently but regression of metastatic disease is rare.49 When patients are treated with ketoconazole, adrenal insufficiency is avoided by decreasing the dose sufficiently to maintain normal cortisol levels. The most frequent adverse reactions with ketoconazole are nausea and vomiting, abdominal pain, and pruritus in 1 to 3% of patients. Hepatotoxicity, primarily of the hepatocellular type, has been associated with its use.48

Aminoglutethimide inhibits cholesterol side-chain cleavage and the conversion of cholesterol to pregnenolone in the adrenal cortex. As a consequence, the synthesis of cortisol, aldosterone, and androgens is suppressed. The drug has been used both in adults and children in doses of 500 to 2,000 mg/d. Cortisol levels fall gradually with regression of the clinical manifestations of Cushing’s syndrome.50 Eventually, patients may need cortisol replacement. The effect of aminoglutethimide is promptly reversed by interruption of therapy. Aminoglutethimide causes gastrointestinal (anorexia, nausea, vomiting) and neurologic (lethargy, sedation, blurred vision) side effects and can cause hypothyroidism in 5% of patients. A skin rash is frequently observed during the first 10 days of treatment, but it usually subsides with continuation of treatment. Headaches have also been observed with the larger doses.

Future Prospects

The prognosis of patients with adrenal cortical carcinoma is poor, but the life expectancy of patients in stages I, II, and III can be significantly extended by a combination of surgical resection and chemotherapy. There are individual cases in whom curative resection has been possible and whose metastatic lesions have regressed on chemotherapy. Early diagnosis is possible in patients with functioning neoplasms, in whom the metabolic manifestations of hormone excess can lead to the discovery of tumors in stages I and II. In contrast, the prognosis of patients in stage IV is grim.

The difficulty in assessing the effectiveness of published treatment protocols stems from the fact that most series are limited in the number of patients studied. There is great variability in the drugs used, the stage and extent of the tumor, and the grade of malignancy. Because adrenal cancer is rare, collaborative, worldwide, multi-center controlled studies will be necessary in order to reach consensus on the efficacy and safety of treatment protocols.

More effective therapy is needed for adrenal cortical carcinomas, and it is likely to come from a better understanding of tumor biology, including the oncogenic and tumorigenic processes that induce early mutations and that drive progression with growth and dissemination of an established tumor. Future approaches to the treatment of adrenal cortical carcinoma are likely to be based on blocking or reversing the biologic mechanisms of tumorigenesis.

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© 2000, BC Decker Inc.
Bookshelf ID: NBK20895

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