Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Abstract

Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with the current gold standard being the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins are promising not only as it comes to identifying malignancy but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.

Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas

“…In this study, we confirmed that IGF2 is an important marker for ACC, but as also previously described in a number of studies, does not fully discriminate ACCs from ACAs (Creemers et al 2016). Mean sensitivity and specificity for diagnosing malignancy are both around 80%, with substantial variances between studies.…”

Antisecretive and Antitumor Activity of Abiraterone Acetate in Human Adrenocortical Cancer: A Preclinical Study

“…A key molecular event that contributes to ACC formation and aggressiveness is the constitutive activation of the Wnt/β-catenin signaling pathway due to mutation of the CTNNB1 gene [2,3]. Approximately 50% of ACC in adults are hormone-secreting tumors that produce cortisol (Cushing's syndrome) or androgen or multiple steroids [4].…”

The next step: mechanisms driving adrenocortical carcinoma metastasis

“…ACC is a rare endocrine malignancy with a high risk of relapse and metastatization even when the primary tumor is diagnosed and surgically removed at an early stage (Else et al 2014, Creemers et al 2016. Current treatments for ACC have only a limited efficacy when disease is at an advanced stage and rely upon use of the adrenolytic agent mitotane (Terzolo et al 2007) and of combination chemotherapy in patients with progressive disease .…”

“…The cornerstone for the treatment of metastatic disease is mitotane (o,p′-DDD), a drug provided with both antihormonal and antitumoral activities (Terzolo et al 2007, Else et al 2014, Creemers et al 2016). This compound is commonly associated with EDP polychemotherapy in patients with rapidly progressive disease, but this regimen does not substantially improve OS of patients .…”