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There have been significant advances in the pathogenesis, diagnosis and management of adrenal tumors during the last 20 years (1, 2). Also, the discovery of clinically silent, incidentally detected adrenal tumors is higher than in the past due to wide application of sensitive imaging procedures, such as computerized tomography (CT) and magnetic resonance imaging (MRI) (3). In the face of the potential fatal outcome of malignant adrenocortical tumors, it is imperative that the physician recognizes the clinical manifestations of these tumors as early as possible, leading to an earlier diagnosis, prompt intervention, and improved survival.

Adrenocortical tumors are divided into benign and malignant groups. The latter group is rare, accounts for 0.05-0.2% of all cancers, with an approximate incidence of 2 new cases per million of population per year (4, 5). However, for unknown reasons the incidence of adrenocortical carcinomas have been much higher in specific geographic regions, such as in Southern and Southwestern Brazil (6-8).

Adrenocortical carcinoma occurs at all ages, from early infancy to the seventh and eight decades of life (9-16). A bimodal age distribution has been reported with the first peak occurring before age 5, and the second in the fourth to fifth decade (17). In all published series, females clearly predominate, accounting for 65 to 90 percent of the reported cases (2). Whereas some investigators report a left-sided prevalence, others note a right-sided preponderance. Bilaterality has been reported in 2 to 10 percent of the cases (2, 14).

CLINICAL PRESENTATION

Adrenocortical tumors can be hormonally silent or hormone-secreting. The vast majority of adrenocortical tumors are benign and hormonally silent. Patients with hormone-secreting adrenocortical neoplasms have associated endocrine syndromes that result from secretion of cortisol and its precursors, adrenal androgens and their precursors, or, rarely, estrogen or mineralocorticoids (Table 1). The most common syndrome associated with adrenal tumors in adults is Cushing's syndrome (2, 7, 17). It is present in 30-40% of patients with adrenocortical carcinoma.

Patients with adrenal adenomas usually have gradual onset of signs of hormone hypersecretion. In contrast, patients with adrenocortical carcinoma tend to have a more acute and progressive course, and virizing effects may predominate.

Virilization occurs in 20-30% of adults with functional adrenal neoplasms, while it is the most common hormonal syndrome in children with adrenocortical tumors (2, 6, 7, 13, 15). Virilization is secondary to hypersecretion of adrenal androgens, including dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S), D5-androstenediol, and D4-androstenedione, all of which may be converted finally to testosterone and 5a-dihydrotestosterone (Table 1). The signs and symptoms in adult females include oligo-amenorrhea, hirsutism, cystic acne, excessive muscle mass, temporal balding, increased of libido, and clitoromegaly. In young girls heterosexual precocious puberty occurs. Combination of Cushing's syndrome and virilization is seen in 10-30% of the patients (2, 3). This combined syndrome is usually associated with secretion of multiple steroid precursors.

Feminization and hyperaldosteronism, as pure hormonal syndromes, are quite rare manifestations of adrenocortical neoplasms. Even more unusual presentations of adrenal cancers include hypoglycemia, non-glucocorticoid-related insulin resistance, and polycythemia (14). The hypoglycemia in adrenocortical carcinoma has been associated with the production of insulin-like growth factor II (IGF-II) (18).

Slightly over half of the adult patients with adrenocortical carcinoma have no recognizable endocrine syndrome. These patients present either with abdominal pain or fullness, or with the incidental finding of an adrenal mass on imaging studies done for unrelated reasons (Table 2). A palpable abdominal mass is present in about half of the patients with nonfunctional adrenocortical carcinoma at the time of diagnosis (2). Finally, metastatic disease may cause symptoms before a primary diagnosis is established in a significant proportion of the patients (14). Local invasion commonly involves the kidneys and inferior vena cava, while metastatic disease may be found in the retroperitoneal lymph nodes, lungs, liver, or bone.

There are several recognized genetic syndromes that have been associated with adrenocortical tumors (Table 3). Most of them could explain the origin of the familial adrenocortical tumors and the unusual associations with other tumors and/or abnormal conditions (2).

LABORATORY STUDIES

Several plasma and urinary steroids are elevated in patients with Cushing's syndrome due to functioning adrenocortical tumors (Table 1). These include cortisol following dexamethasone suppression test, DHEA, DHEAS, D5-androstenediol, D4-androstenedione, pregnenolone, 17-hydroxypregnenolone, and 11-deoxycortisol in the plasma, and free cortisol, 17-hydroxysteroids, 17-ketosteroids and the tetrahydro metabolite of 11-deoxycortisol in the urine (2). Despite the fact that steroidogenic precursors, such as 17-hydroxyprogesterone and 11-deoxycortisol, are not essential in the evaluation of hypercortisolism, they may occasionally provide clues to the presence of an adrenal malignancy in patients with Cushing's syndrome (7). Generally, many of the steroid biosynthesis enzymes are defective in adrenocortical carcinomas, providing an inefficient machinery for steroid production, and associated with plasma patterns of steroid precursors typical of enzymatic blocks (7).

A low plasma adrenocorticotropic hormone (ACTH) level, associated with elevated concurrent plasma cortisol concentration, is indicative of autonomous activity of the adrenal glands (19). There are several dynamic endocrine tests for the differential diagnosis of adrenal Cushing's syndrome from the ACTH-dependent forms of the condition (19). These include the classic high dose dexamethasone suppression test and the ovine corticotropin releasing hormone (CRH) stimulation test. Typically, both tests are associated with lack of responsiveness of cortisol secretion to dexamethasone and CRH.

The clinical diagnosis of adrenally-induced virilization may be confirmed by measurement of plasma adrenal androgens and testosterone and 24h urinary excretion of 17-ketosteroids (Table 1). Feminization or hyperaldosteronism can be confirmed by measurements of elevated plasma estradiol and/or estrone, or aldosterone and PRA, 11-deoxycorticorticosterone and/or corticosterone, respectively. Finally, patients with hypoglycemic attacks should be submitted to IGF-II measurement.

All patients, and particularly those with "nonfunctional" adrenal masses, should also be screened for pheochromocytoma, even in the absence of sustained hypertension.

IMAGING PROCEDURES

The diagnosis of adrenal neoplasms depends on the identification of an adrenal mass on computed tomography (CT) and/or magnetic resonance imaging (MRI). Both normal and abnormal adrenal glands are easily visible on CT, because of the adipose tissue that surrounds these glands in the retroperitoneum (20, 21). The presence of a large unilateral adrenal mass with irregular borders is virtually diagnostic of adrenal cancer. CT provides information about size, homogeneity, presence of calcifications, areas of necrosis and about the extend of local invasion, thus also being helpful in making decisions about the resectability of the lesion (22). Tumors as small as 0.5 cm have been detected by CT, although the relative lack of retroperitoneal fat in children might decrease the sensitivity of the test in this age group (21, 22).

Whether MRI will prove to be superior to CT scanning in diagnosing and differentiating adrenal masses remains to be seen. MRI provides information about 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 be identified occasionally (23, 24). Some authors have reported that MRI can distinguish, with a fair degree of accuracy, between 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 liver (24). Thus, primary malignant adrenocortical lesions have an intermediate to high signal intensity on T2-weighted images. Nonfunctional adenomas have low signal intensity, whereas pheochromocytomas have an extremely high signal intensity.

The size of the adrenal tumor plays an important role in the indications for surgical excision of non-functioning adrenal tumors and selecting the best surgical approach. Recently it was demonstrated that both MRI and CT significantly understimated the true size of adrenal tumors larger than 3 cm by 20 and 18%, respectively, indicating that these methods of pre-operative sizing of adrenal lesions should be interpreted with caution (25).

Positron emission tomography with F-18-fluorodeoxyglucose (FDG-PET) is an accurate non-invasive method which has been useful for initial staging as well as for follow up of adrenocortical tumors (26, 27). Meta-analysis of the efficacy of FDG-PET in adrenal metastases patients showed sensitivity 96%, specificity 99% and accuracy 98% (27). In addition, recurrence of adrenocortical tumors was also accurately detected by this method.

Other imaging modalities, such as iodo-cholesterol scanning, venography and arteriography, are rarely indicated. The 125iodo-cholesterol scan is usually negative in malignant adrenocortical neoplasms and positive in steroid-secreting adenomas. 125Iodo-cholesterol uptake may help define whether there is unilateral or bilateral autonomous steroidosynthetic tissue, since adrenal masses are seen bilaterally in the latter on CT or MRI imaging. Also, it may help with the localization of adrenal rests or adrenal remnants after adrenalectomy. On occasion, selective arteriography may help distinguish between adrenal masses and upper pole renal tumors. Inferior vena cava venography may be indicated if CT or MRI findings suggest presence of a tumor thrombus in this vessel. In general, these invasive techniques are reserved for the rare instance in which CT or MRI cannot supply the information needed.

PATHOLOGY, STAGING, PROGNOSIS

Histologically, adrenocortical tumors consist of lipid-depleted cells with granular cytoplasm and large multiple nuclei and nucleoli (28-29). Tumor cells have varying mitotic activity. The differentiation of benign from malignant adrenocortical neoplasms solely on the basis of histologic findings is difficult, if not impossible. Thus, several reports demonstrated that patients whose operatively excised tumors exhibited histologically benign features, subsequently developed local recurrences or distant metastases, whereas others, whose tumors had a microscopic appearance typical of malignancy lived tumor-free for many years.

Several macroscopic and microscopic criteria are collectively used to define the malignancy of an adrenocortical tumor and to predict its behavior (29). Macroscopically, wet weight of >500 g, a grossly lobulated cut surface, the presence of necrotic areas and/or calcifications and intratumor hemorrhages predict malignancy. Microscopically, architectural disarray, frequent mitoses, marked cellular pleomorphism, nuclear atypia and hyperchromasia, as well as invasion of the capsule, suggest malignancy.

Abnormal DNA contents have been detected in adrenocortical carcinomas by flow cytometric DNA analysis (30, 31). Aneuploidy occurs in neoplastic subpopulations through genetic instability and mitotic irregularities. Bowlby et al. (30) reported that 83% of carcinomas showed aneuploidy, suggesting that flow cytometric analysis may prove to be a complement to the conventional histopathologic methods and a valuable tool in predicting the prognosis of patients with adrenocortical tumors.

Molecular markers for malignancy, such as the presence of alterations in the p53 tumor suppressor gene, expression of the proliferation-associated antigen Ki67, the rate of apoptotic tumor cells and loss of hetrozygosity were recently studied in normal adrenals, hyperplasia, adenomas and carcinomas of adrenal cortex (32). Only the Ki67 index was a sensitive and specific indicator of adrenocortical carcinoma, and could be useful in discerning of adrenocortical carcinoma from benign adenomas. An extensive review on the molecular pathogenesis of adrenal tumors is provided in reference 33.

The staging system for adrenocortical carcinomas depends upon tumor size, nodal involvement, invasion of adjacent organs, and presence of distant metastases (Table 4) (2). Staging is helpful in defining prognosis and therapy. Only patients with stage I and II disease are curable with surgery. Unfortunately, the great majority of the patients have either stage III or IV disease at the time of diagnosis. Despite complete resection, virtually 100% of patients with stage III disease have recurrent and metastatic disease within 5 years of tumor resection. Moreover, the five year survival for stage III adrenal carcinoma is generally less than 30%. The most frequent sites of metastasis are lymph nodes (25-46%), lungs (47%-97%), liver (53%-68%), abdomen (33-43%), and bones (11-33%) (Table 5). Metastases have been reported in the ovary, spleen, pleura, thyroid, pharynx, tonsils, mediastinum, myocardium, brain, spinal cord, skin, and subcutaneous tissue (2) Despite aggressive surgical therapy, the mean five-year survival of patients with stage IV disease is 15-25%.

TREATMENT

Surgical resection is the only therapy that cures or prolongs survival significantly, particularly if the disease is detected at stages I and II (8, 14, 17). Radical excision with "en bloc resection" of any local invasion offers the best chance for cure. A wide exposure is needed, utilizing an extended subcostal incision or a thoracoabdominal approach. Patients apparently cured with surgery require continued surveillance. After complete macroscopic resection in stage III and IV disease Mitotane^® may be given to increase the duration between recurrences. However, this has not been tested in a controlled study (34, 35).

Mitotane has been used extensively in patients with adrenocortical carcinoma, however this drug has been generally ineffective in prolonging overall survival (34). Mitotane acts as an adrenolytic agent, possibly by causing alterations in mitochondrial function, blocking adrenal steroid 11-b-hydroxylation and altering the extra-adrenal metabolism of cortisol and androgens. Studies demonstrated that high oral doses (up to 12-14 g/day) of mitotane caused remission of hypercortisolism in 50-60% of patients with adrenocortical carcinoma, however, short-lived 6-10 mo objective tumor responses occurred in less than 20% of these patients (34, 35). The side effects of mitotane are largely dose-related (Table 6). Weakness, somnolence, confusion, lethargy, and headache are reported in half of the patients treated (2). More serious neurotoxicity, such as ataxia and dysarthria, may also occur. Gastrointestinal side effects include anorexia, nausea, and diarrhea, which are present in most patients. Skin rash, toxic retinopathy with papilledema, and interstitial cystitis are less commonly seen. Total cholesterol frequently increases with treatment and reaches levels so high that specific therapy may be advised in some patients.

To avoid toxicity low doses of mitotane (2-3 g daily) were recently used in patients with adrenocortical carcinoma (36, 37). The dose adjustments were guided by the monitoring of plasma mitotane levels in these patients, which reached "therapeutic" concentrations (defined as mitotane plasma levels between 14-20 mcg/mL).

Several alternative chemotherapeutic regimens have been used for the treatment of metastatic adrenocortical carcinomas. They include cisplatin, etoposide, 5-fluorouracil, doxorubicin, vincristine, gossipol, suramin, and melphalan (38-43). Gossipol, a spermatoxin derived from crude cottonseed oil, inhibits the growth of human adrenocortical tumors in nude mice. Oral gossipol (30-70 mg/day) was used with relative safely in outpatients with metastatic adrenal cancer, however a partial tumor response rate was observed in only 17% (38). This is consistent with the generally poor response of adrenal cancer to most medical therapies. Part of this refractoriness may be explained by the fact that adrenocortical carcinomas express the multidrug-resistance gene MDR-1.

Chemotherapy with multiple agents has been tested in smaller series and has resulted in significant side effects. One of the best results was achieved by the combination of etoposide, doxorubicin, and cisplatin associated with mitotane (44). This combination achieves a response rate of 54%, including individual complete responses.

A Southwest Oncology Group Study demonstrated a 30% response rate with the combination of cisplatin and mitotane in patients with metastatic adrenocortical carcinoma (45, 46). More recently, the same group also evaluated the effect of the combination of cisplatin and etoposide followed by mitotane on disease progression in patients with locally advanced or metastatic adrenocortical carcinoma. Responses were noted in 11% of the 45 patients studied and the median survival was only 10 months (46). These data are typical. The therapeutic management of advanced adrenocortical carcinoma usually causes disappointment and frustration in both the patient and the physician. This condition makes the early detection of these tumors and the discovery of new effective therapeutic modalities imperative. To make progress in treating advanced adrenocortical carcinomas, muticenter trials must be encouraged.