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BACKGROUND AND PRESENTATION

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Adrenocortical carcinoma (ACC) is a rare malignancy, affecting 1.5–2 persons per million each year (1). ACC is slightly more common in women and has a bimodal age distribution, with a higher incidence in children younger than 5 years and in adults in their 4th and 5th decades of life (1). Despite improved methods of diagnosis, ACC usually presents at an advanced stage and as a result 5-year survival ranges from 20% and 45%.

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At the time of disease discovery there may be no symptoms (the tumor may be found incidentally on imaging). In other patients there may be symptoms of hormone excess or complaints referable to an abdominal mass. Hormone excess presents clinically as Cushing's syndrome, virilization, feminization, or, less frequently, hypertension with hypokalemia. Hormone hypersecretion can be found in as many as 73%–79% of ACC patients, although not all patients have symptoms (2). In one study, amongst 45 ACC patients, routine biochemistry documented hormone excess in 33 (73%) with excess glucocorticoid and adrenal androgen in 12, isolated glucocorticoid in 11, isolated adrenal androgen in 7, and 17β-estradiol excess in combination with glucocorticoid and adrenal androgen excess in two and one, respectively. Steroid profiling revealed predominantly immature, early-stage steroid precursors, and their production most likely a consequence of altered expression of steroidogenic enzymes in variably undifferentiated tumors. While the classification of ACCs by hormone profile has limited value, hormone secretion, especially cortisol, may be an independent predictor of poor prognosis (3)—although not all studies agree with this conclusion (4). Older age at diagnosis, stage III (local lymph nodes) and IV (local organ invasion or distant metastases) disease and cortisol hypersecretion are risk factors significantly associated with a shorter survival (3). The poorer prognosis of cortisol-secreting tumors could be attributed to the comorbidity of cortisol hypersecretion, the immunosuppressive effects of excess cortisol possibly favoring development of the tumor and its metastases, or cortisol-mediated metabolic changes that favor the growth of a more aggressive tumor.

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GENETICS

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Although most ACC lack identifiable risk factors, heredity plays a role in some patients (5). Risk factors include the Li-Fraumeni syndrome (LFS), multiple endocrine neoplasia type 1 (MEN1), familial adenomatous polyposis coli (Gardner syndrome), and the Beckwith-Wiedemann syndrome (BWS) (6). Predisposition is thought to arise from mutations in p53, MEN1, APC, or CDKN1C suppressor genes or dysregulation of the CDKN1C tumor suppressor gene. A unique risk factor has been described in southern and southeastern Brazil. There, a high frequency of an endemic germline p53 R337H mutation is responsible for the highest known incidence of childhood ACC—with a founder germline R337H mutation found in 95% of ACCs reported in young children (7). The frequency of this germline R337H mutation is due to a common ancestor, a conclusion supported by the fact that no case of a de novo R337H ...

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