Adrenocortical carcinoma (ACC) is a rare but often aggressive endocrine malignancy that may present with symptoms of hormone secretion, as a symptomatic nonfunctional abdominal mass, or as an incidental imaging finding. The first known successful adrenal cancer resection was performed by Knowsley Thornton in 1890.1,2 In the same year, Otto Ramsay published a small case series of patients with malignant adrenal tumors.3 However, prognosis was poor as tumor excision offered only temporarily relief with the majority of patients suffering from severe adrenal insufficiency. In 1949, discovery of cortisone, derived from an adrenocortical extract developed by the Mayo group, significantly improved survival from adrenalectomy.4 Other milestones include the introduction of mitotane, a pesticide derivative, which was first used in 1960 to treat inoperable or recurrent ACC.5
Adrenocortical carcinoma is rare with an annual incidence of 1 to 2 per million people.6,7 Higher incidence of ACC is seen in the pediatric population in southern Brazil who are at higher risk due to an inherited germline p53 mutation.8 Adrenal tumors are found incidentally in over 4% of abdominal imaging studies.9 From a retrospective review from the Mayo Clinic, ACC constitutes 1.2% of all incidentalomas.10 There is a preponderance of women, ranging from 55% to 60% of those affected by ACC. The age distribution is bimodal with peaks in children under the age of five and in adults in the fourth and fifth decades of life.11
Though most ACC are sporadic in nature, it is associated with several hereditary syndromes.12 Li–Fraumeni syndrome, caused by germline mutations of the tumor suppressor gene, TP53, is found in 50% to 80% of children and about 4% of adults with ACC.13,14 Patients with Beckwith–Wiedemann syndrome have 11p15 mutations and are predisposed to Wilms' tumor, neuroblastoma, hepatoblastoma, and ACC. Inactivating mutations of the menin gene causes multiple endocrine neoplasia type 1 (MEN1) syndrome, which is commonly associated with parathyroid, pancreatic neuroendocrine, and pituitary tumors. Adrenal tumors occur in about 5% of patients with MEN1; most are adenomas, but rarely can be ACC.
Somatic mutations have been found in sporadic ACC. Loss of heterozygosity (LOH) at the 17p13 locus, TP53, is found in more than 50% of ACC in adult patients and is associated with an aggressive phenotype.15 Overexpression of IGFII due to LOH at 11p15 is also associated with malignancy in sporadic ACC.16 Inhibition of the IGF pathway in vitro leads to decreased cell proliferation in ACC.17 Wnt/beta-catenin signaling is another important pathway during embryonic adrenal development, and the constitutive activation through mutation of the CTNNB1 gene has been implicated in adrenal tumorigenesis.18 Mutations in CTNNB1 in animal models have shown to induce adrenal hyperplasia and predispose to ACC.19 Activation of the Wnt/beta-catenin pathway is ...