Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, often with an unfavorable prognosis. Here we summarize the knowledge about diagnosis, epidemiology, pathophysiology, and therapy of ACC. Over recent years, multidisciplinary clinics have formed and the first international treatment trials have been conducted. This review focuses on evidence gained from recent basic science and clinical research and provides perspectives from the experience of a large multidisciplinary clinic dedicated to the care of patients with ACC.

Untreated Cushing’s disease and the resultant chronically elevated glucocorticoid levels lead to severe metabolic disturbances, including diabetes mellitus, obesity, hypertension, muscle wasting, and osteoporosis. Although transsphenoidal resection has become the standard of care for Cushing’s disease with high initial success rates, little information is available on the long-term morbidity and mortality of patients in remission compared with patients with recurrent or persistent Cushing’s disease after such treatment. We therefore conducted a retrospective study of 289 patients with Cushing’s disease who underwent transsphenoidal microsurgery for an ACTH-secreting adenoma at a tertiary care center exclusively by one surgeon (C.B.W.). Postoperative remission was achieved in 82% (n = 236) of patients, with best initial remission rates observed in patients with grade I (86%) and II (83%) or stage 0 (88%), A (94%), and B (100%) tumors. Male gender, larger tumor size, and higher stage predicted poorer initial outcome. Long-term follow-up was obtained on 178 patients, with a median follow-up time of 11.1 yr (range, 0.6–24.1 yr). Thirteen of 150 (9%) of patients in initial remission developed recurrent disease, and 12 patients underwent additional treatment. At last follow-up, only two of these patients had active disease. However, of the 28 patients with initial persistent disease who had follow-up greater than 6 months, 10 patients continued to have active disease at last follow-up. Although overall survival rates in patients with initial remission did not differ significantly from expected compared with the general population based on age and sex distribution, patients with initial persistent disease had a significant increase in mortality compared with the expected mortality. Thus, successful treatment of Cushing’s disease is associated with normal long-term survival. These results suggest that patients with persistent Cushing’s disease require early and aggressive intervention to attempt to prevent this excess mortality.

The nuclear receptor steroidogenic factor 1 (Sf1, Nr5a1) is essential for adrenal development and regulates genes that specify differentiated adrenocortical function. The transcriptional coactivator β-catenin reportedly synergizes with Sf1 to regulate a subset of these target genes; moreover, Wnt family members, signaling via β-catenin, are also implicated in adrenocortical development. To investigate the role ofβ -catenin in the adrenal cortex, we used two Sf1/Cre transgenes to inactivate conditional β-catenin alleles. Inactivation of β-catenin mediated by Sf1/Cre^high, a transgene expressed at high levels, caused adrenal aplasia in newborn mice. Analysis of fetal adrenal development with Sf1/Cre^high-mediated β-catenin inactivation showed decreased proliferation in presumptive adrenocortical precursor cells. By contrast, the Sf1/Cre^low transgene effected a lesser degree of β-catenin inactivation that did not affect all adrenocortical cells, permitting adrenal survival to reveal age-dependent degeneration of the cortex. These results define crucial roles for β-catenin - presumably as part of the Wnt canonical signaling pathway - in both embryonic development of the adrenal cortex and in maintenance of the adult organ.

Context: Drug therapy for adrenocortical carcinoma (ACC), a rare and lethal malignancy, is largely empirical and ineffective. New treatments directed at molecular targets critical to the pathophysiology of ACC may prove more efficacious. Objective: The objective of the study was to profile human adrenal tumors and ACC cell lines to assess activated IGF signaling and determine the efficacy of two IGF receptor (IGF-1R) antagonists alone and in combination with mitotane. Experimental Design: ACC cell lines that display or lack activated IGF signaling are used to assess the effects of two IGF-1R antagonists in cultured cells and ACC xenograft tumors. Results: Transcriptional profiling data derived from DNA microarray analysis of human adrenal tumors implicate IGF2 as the single highest up-regulated transcript in the vast majority of carcinomas. We show that the majority of ACC cell lines tested display constitutive IGF ligand production and activation of downstream effector pathways. Both IGF-1R antagonists cause significant dose-dependent growth inhibition in ACC cell lines. Furthermore, we observe that mitotane, the first-line adrenolytic drug used in patients with ACC, results in enhanced growth inhibition when used in combination with the IGF-1R antagonists. We next examined the activity of IGF-1R antagonists against ACC xenografts in athymic nude mice. IGF inhibition markedly reduced tumor growth greater than that observed with mitotane treatment, and combination therapy with mitotane significantly enhanced tumor growth suppression. Conclusion: These findings establish a critical role of IGF signaling in ACC pathophysiology and provide rationale for use of targeted IGF-1R antagonists to treat adrenocortical carcinoma in future clinical trials.