Management of Adrenocortical Carcinoma

Bruno Allolio; Stefanie Hahner; Dirk Weismann; Martin Fassnacht


Clin Endocrinol. 2004;60(3) 

In This Article


The molecular pathogenesis of adrenal tumours has been the topic of recent reviews (Reincke, 1998; Kjellman et al., 2001; Kirschner, 2002; Koch et al., 2002). Despite significant advances in the understanding of adrenal tumour development the underlying sequence of events remains to be elucidated. Some insight comes from hereditary tumour syndromes associated with the development of adrenocortical cancer. In the Li-Fraumeni syndrome the frequency of ACC is about 1% (Sameshima et al., 1992). Affected patients have germline mutations of the p53 tumour suppressor gene located at the 17p13 locus (Malkin et al., 1990; Wagner et al., 1994) and may develop a variety of malignancies (e.g. breast cancer, sarcomas). In the tumour, the second p53 allele is inactivated by a somatic mutation leading to complete loss of wild-type p53 activity (McNicol et al., 1997a, 1997b). An exciting recent observation is the demonstration of a specific germline point mutation of p53 encoding an R337H amino acid substitution in children with ACC from Brazil (Ribeiro et al., 2001). In contrast to patients with the typical Li-Fraumeni syndrome, only ACC has been associated with this mutation indicating a tissue-specific effect. This is the first demonstration of a germline p53 mutation, which contributes to cancer in a tissue-specific manner (DiGiammarino et al., 2002). Intriguingly, the mutated R337H p53 protein functioned normally in some in vitro studies. However, it was found that the function changed in a pH-sensitive and temperature-dependent manner (Lee et al., 2003). How these physico-chemical abnormalities predispose to ACC remains to be elucidated (Hainaut, 2002). Mutations in the p53 gene have also been demonstrated in a large percentage of patients with sporadic ACC (Reincke et al., 1994; Barzon et al., 2001; Gicquel et al., 2001; Wachenfeld et al., 2001) and accumulation of abnormal p53 protein correlates with a more aggressive clinical behaviour in ACC (Sredni et al., 2003).

Another hereditary syndrome associated with ACC is the Beckwith-Wiedeman syndrome (BWS). BWS has been mapped to the 11p15·5 region and is associated also with other malignancies (e.g. Wilm's tumour, hepatoblastoma). The 11p15·5. locus includes the IGF-II, H19, and p57/Kip2 genes which show functional imprinting. Whereas normally the paternal IGF-II allele is transcribed, H19 and the p57 tumour suppressor gene are expressed by the maternal allele (Koch et al., 2002). Uniparental paternal isodisomy for this locus associated with IGF-II overexpression has been found in BWS. Similarly, in sporadic ACC rearrangement at the 11p15 locus with overexpression of IGF-II is frequently observed caused either by duplications of the paternal 11p15 allele or by loss of the maternal allele containing the H19 gene, which is involved in IGF-II suppression (Hao et al., 1993; Ilvesmaki et al., 1993; Gicquel et al., 1994, Gicquel et al., 1997; Leighton et al., 1995; Weber et al., 2000). Increased expression of IGF-II was recently also demonstrated by Giordano et al. (2003) in 90% of sporadic ACCs using DNA microarray analysis. The magnitude of increased IGF-II expression and the lack of other signal transduction related changes observed in this transcriptional survey suggest that IGF-II overexpression is of particular importance for ACC progression and therefore may be a promising therapeutic target. However, this new technical approach not only confirmed the role of IGF-II but also identified some other genes that might be relevant to ACC pathogenesis (e.g. cyclins).

Of interest is also the role of pro-opiomelanocortin (POMC) and its receptors in adrenal tumourigenesis, as the trophic function of POMC for the adrenals has been well documented. Sequencing of the ACTH receptor (ACTH-R) gene in adrenal tumours did not reveal constitutive activating mutations (Latronico et al., 1995). Tumours rather demonstrated loss of heterozygosity of the ACTH-R with reduced expression of ACTH-R mRNA, in particular in some malignant adrenal tumours (Reincke et al., 1997a, 1997b; Beuschlein et al., 2001). These findings support the concept derived from in vitro studies that ACTH acts as a differentiation factor at the adrenal level. Accordingly, it was recently demonstrated that ACTH inhibits growth of Y1 ACC in mice in vivo (Zwermann et al., 2003). On the other hand, it has been reported that peptides derived from the N-terminus of POMC play a role for adrenal growth (Estivariz et al., 1982; Lowry et al., 1983). These peptides may be activated at the adrenal level by the 'adrenal secretory protease' (AsP; Bicknell et al., 2001). This view is supported by in vitro data demonstrating a growth stimulating effect of N-POMC on adrenocortical cancer cells in vitro via an unknown receptor (Fassnacht et al., 2003). Obviously these findings raise the question whether suppression of POMC (by exogenous glucocorticoids) may play a role in the management of some patients with ACC.

Chromosomal instability has been observed in both benign and malignant adrenal tumours indicating defects in the mitogenic machinery (Dohna et al., 2000). Accordingly, the number of centrosomes is increased (Kjellman et al., 2001). A transition to an aneuploid state has been described in tumours larger than 4 cm, and the genetic alterations detected by comparative genomic hybridization correlate with tumour size and malignancy with frequent gene amplifications (Kjellman et al., 1996, 2001; Dohna et al., 2000).