Chapter 16

Adrenocortical carcinoma (ACC) is a rare malignant endocrine neoplasm with an estimated incidence of 0.5 to 2 cases per 1 million people annually in the United States,1,2 accounting for 0.02% of all cancers reported annually.1 The prognosis for most patients diagnosed with ACC is disappointingly poor because of delays in diagnosis and the absence of effective systemic therapy. Approximately 50% of affected patients do not survive beyond 2 years after diagnosis, and the 5-year mortality rate approaches 80%.3 ACC has a bimodal age distribution with an increased incidence among children younger than 5 years of age and in individuals in their fourth and fifth decades of life. A slightly higher incidence rate is reported for women than for men.4 Approximately 40% of ACCs produce clinically significant excess amounts of steroid hormones, resulting in characteristic signs and symptoms;5 female patients are more likely to have an associated clinical endocrine syndrome. Surgery remains the only effective curative treatment for ACC. In a 1996 study of risk factors, cigarette smoking and the use of oral contraceptives were found to be associated with the development of ACC.6 An association has also been described between ACC and congenital adrenal hyperplasia.7

The etiology of ACC is unknown. A study of adrenocortical tumor clonality reported that whereas most benign adrenocortical lesions were polyclonal, ACCs were monoclonal, thus suggesting that ACC develops through the uncontrolled growth of a single cell.8

ACCs may be sporadic or occur as part of a hereditary tumor syndrome. Investigations of genetic alterations present in adrenocortical tumors have revealed the involvement of multiple chromosomal loci that correlate with regions that are abnormal in familial cancer syndromes. Such loci include those associated with Li-Fraumeni syndrome (LFS; p53 gene on17p13), multiple endocrine neoplasia type I (MEN1; MEN1 gene on 11q13), Beckwith-Wiedemann syndrome (11p15.5, correlated with the overproduction of insulin-like growth factor [IGF] II), and the Carney complex (loss of heterozygosity on 2p16).9

Although a multistep tumor progression model has been suggested in the etiology of sporadic ACC, proof of a hyperplasia-to-adenoma-to-carcinoma sequence is lacking.10,11 Insights into the pathogenesis of sporadic ACC have been gained from the study of familial cancer syndromes that include ACC. For instance, the most frequently inherited p53 mutations associated with LFS are also found in sporadic cases of ACC.12 One of the most common p53 point mutants, Arg 175 to His, fails to bind DNA and results in complete loss of p53 transcriptional activity. Although this mutation presents with a classic LFS cancer spectrum, including ACC, it also accounts for 6% of the missense mutations identified in all human cancers.13 In Brazil, where the rate of pediatric ACC is 10 to 15 times greater than the overall worldwide incidence, the majority of patients have the same germline point mutation of p53 encoding an Arg 337 to His amino acid substitution in exon 10.14...

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