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Purpose: The purpose of this study was to evaluate the capabilities of multiparametric magnetic resonance imaging (MRI) in differentiating between lipid-poor adrenal adenoma (LPAA) and adrenocortical carcinoma (ACC)., Materials and Methods: Patients of two centers who underwent surgical resection of LPAA or ACC after multiparametric MRI were retrospectively included. A training cohort was used to build a diagnostic algorithm obtained through recursive partitioning based on multiparametric MRI variables, including apparent diffusion coefficient and chemical shift signal ratio (i.e., tumor signal intensity index). The diagnostic performances of the multiparametric MRI-based algorithm were evaluated using a validation cohort, alone first and then in association with adrenal tumor size using a cut-off of 4 cm. Performances of the diagnostic algorithm for the diagnosis of ACC vs. LPAA were calculated using pathology as the reference standard., Results: Fifty-four patients (27 with LPAA and 27 with ACC; 37 women; mean age, 48.5 ± 13.3 [standard deviation (SD)] years) were used as the training cohort and 61 patients (24 with LPAA and 37 with ACC; 47 women; mean age, 49 ± 11.7 [SD] years) were used as the validation cohort. In the validation cohort, the diagnostic algorithm yielded best accuracy for the diagnosis of ACC vs. LPAA (75%; 46/61; 95% CI: 55-88) when used without lesion size. Best sensitivity was obtained with the association of the diagnostic algorithm with tumor size (96%; 23/24; 95% CI: 80-99). Best specificity was obtained with the diagnostic algorithm used alone (76%; 28/37; 95% CI: 60-87)., Conclusion: A multiparametric MRI-based diagnostic algorithm that includes apparent diffusion coefficient and tumor signal intensity index helps discriminate between ACC and LPAA with high degrees of specificity and accuracy. The association of the multiparametric MRI-based diagnostic algorithm with adrenal lesion size helps maximize the sensitivity of multiparametric MRI for the diagnosis of ACC., Competing Interests: Declaration of competing interest The authors declare no actual or potential conflict of interest related to this study., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Adrenocortical carcinoma is rare and aggressive endocrine cancer of the adrenal gland. Within adrenocortical carcinoma, a recently described subtype characterized by a CpG island methylator phenotype (CIMP) has been associated with an especially poor prognosis. However, the drivers of CIMP remain unknown. Furthermore, the functional relation between CIMP and poor clinical outcomes of patients with adrenocortical carcinoma stays elusive., Results: Here, we show that CIMP in adrenocortical carcinoma is linked to the increased expression of DNA methyltransferases DNMT1 and DNMT3A driven by a gain of gene copy number and cell hyperproliferation. Importantly, we demonstrate that CIMP contributes to tumor aggressiveness by favoring tumor immune escape. This effect could be at least partially reversed by treatment with the demethylating agent 5-azacytidine., Conclusions: In sum, our findings suggest that co-treatment with demethylating agents might enhance the efficacy of immunotherapy and could represent a novel therapeutic approach for patients with high CIMP adrenocortical carcinoma., (© 2023. The Author(s).)

Purpose of the Report: Adrenocortical carcinoma (ACC) is an extremely rare endocrine malignancy, which cannot always be diagnosed during conventional radiology and hormonal investigations. 18 F-FDG PET could help predict malignancy, but more data are necessary to support future guidelines., Methods: A cohort of 63 patients with histologically proven ACC (n = 55) or metastatic ACC with steroid oversecretion (n = 8) was assembled. All patients underwent an 18 F-FDG PET, and the SUV max and the adrenal-to-liver SUV max ratio were calculated. The 18 F-FDG PET parameters were compared with clinical, pathological, and outcome data., Results: Fifty-six of 63 patients (89%) had an ACC with an adrenal-to-liver SUV max ratio >1.45, which was a previously defined cutoff value to predict malignancy with 100% sensitivity. Seven ACCs (11%) had a lower uptake (adrenal-to-liver SUV max <1.45), most of them with a proliferation marker Ki-67 expression level <10%. A positive correlation between 18 F-FDG PET parameters (SUV max and adrenal-to-liver SUV max ratio) and tumor size, ENSAT (European Network for the Study of Adrenal Tumors) staging, total Weiss score, and the Ki-67 was found. The strong correlation between SUV max and Ki-67 ( r = 0.47, P = 0.0009) suggests a relationship between 18 F-FDG uptake levels and tumor proliferation. No statistically significant associations between outcome parameters (progression-free or overall survival) and 18 F-FDG PET parameters were found., Conclusions: This large cohort study shows that most cases of ACC demonstrate high 18 F-FDG uptake. However, the positive correlation observed between SUV max and Ki-67 expression levels seems to explain the possibility of identifying some ACC with a low or inexistent 18 F-FDG uptake. These findings have practical implications for the management of patients with an adrenal mass., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

Background: EZH2 is overexpressed and associated with poor prognosis in adrenocortical carcinoma (ACC) and its inhibition reduces growth and aggressiveness of ACC cells in culture. Although EZH2 was identified as the methyltransferase that deposits the repressive H3K27me3 histone mark, it can cooperate with transcription factors to stimulate gene transcription., Methods: We used bioinformatics approaches on gene expression data from three cohorts of patients and a mouse model of EZH2 ablation, to identify targets and mode of action of EZH2 in ACC. This was followed by ChIP and functional assays to evaluate contribution of identified targets to ACC pathogenesis., Results: We show that EZH2 mostly works as a transcriptional inducer in ACC, through cooperation with the transcription factor E2F1 and identify three positive targets involved in cell cycle regulation and mitosis i.e., RRM2, PTTG1 and ASE1/PRC1. Overexpression of these genes is associated with poor prognosis, suggesting a potential role in acquisition of aggressive ACC features. Pharmacological and siRNA-mediated inhibition of RRM2 blocks cell proliferation, induces apoptosis and inhibits cell migration, suggesting that it may be an interesting target in ACC., Conclusions: Altogether, these data show an unexpected role of EZH2 and E2F1 in stimulating expression of genes associated with ACC aggressiveness.

Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with overall poor prognosis. The Ki67 labeling index (LI) has a major prognostic role in localized ACC after complete resection, but its estimates may suffer from considerable intra- and interobserver variability. VAV2 overexpression induced by increased Steroidogenic Factor-1 dosage is an essential factor driving ACC tumor cell invasion., Objective: To assess the prognostic role of VAV2 expression in ACC by investigation of a large cohort of patients., Design, Setting, and Participants: A total of 171 ACC cases (157 primary tumors, six local recurrences, eight metastases) from seven European Network for the Study of Adrenal Tumors centers were studied., Outcome Measurements: H-scores were generated to quantify VAV2 expression. VAV2 expression was divided into two categories: low (H-score, <2) and high (H-score, ≥2). The Ki67 LI retrieved from patients' pathology records was also categorized into low (<20%) and high (≥20%). Clinical and immunohistochemical markers were correlated with progression-free survival (PFS) and overall survival (OS)., Results: VAV2 expression and Ki67 LI were significantly correlated with each other and with PFS and OS. Heterogeneity of VAV2 expression inside the same tumor was very low. Combined assessment of VAV2 expression and Ki67 LI improved patient stratification to low-risk and high-risk groups., Conclusion: Combined assessment of Ki67 LI and VAV2 expression improves prognostic prediction in ACC., (Copyright © 2017 Endocrine Society)

New European guidelines for the management of adrenal incidentalomas were recently released. One of the most novel recommendations is to stop following patients when they present a typical, small and non-secreting adenoma. We report here the case of a 71-year-old man with such an adenoma, who developed an adrenocortical carcinoma (ACC) fourteen years later, with subsequent metastases and death. Clinically, he had a normal blood pressure and no sign of hormonal hypersecretion. The hormonal work-up showed no hormone excess: urinary free cortisol level was normal, the diurnal cortisol rhythm was respected and urinary catecholamine metabolites levels were normal. Computed tomography (CT) scan showed a homogeneous lesion, with a low density. The lesion remained unchanged during the five years of follow-up. Eight years after the last CT, a large right heterogeneous adrenal mass was incidentally discovered during an ultrasound examination. On CT scan, it was a 6 cm heterogeneous tumor. On hormonal work-up, there was no secretion. The patient was operated of an adrenalectomy, and the histology described an ACC with a Weiss score at 8, with no benign contingent. To our knowledge, this is the first case of an ACC occurring in a patient with prior adrenal imaging showing a typical benign adenoma., (© 2017 European Society of Endocrinology.)

Germline alterations in DNA repair genes are implicated in cancer predisposition and can result in characteristic mutational signatures. However, specific mutational signatures associated with base excision repair (BER) defects remain to be characterized. Here, by analysing a series of colorectal cancers (CRCs) using exome sequencing, we identified a particular spectrum of somatic mutations characterized by an enrichment of C > A transversions in NpCpA or NpCpT contexts in three tumours from a MUTYH-associated polyposis (MAP) patient and in two cases harbouring pathogenic germline MUTYH mutations. In two series of adrenocortical carcinomas (ACCs), we identified four tumours with a similar signature also presenting germline MUTYH mutations. Taken together, these findings demonstrate that MUTYH inactivation results in a particular mutational signature, which may serve as a useful marker of BER-related genomic instability in new cancer types. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Insulin-like growth factor 2 (IGF2) overexpression is an important molecular marker of adrenocortical carcinoma (ACC), which is a rare but devastating endocrine cancer. It is not clear whether IGF2 overexpression modifies the biology and growth of this cancer, thus more studies are required before IGF2 can be considered as a major therapeutic target. We compared the phenotypical, clinical, biological, and molecular characteristics of ACC with or without the overexpression of IGF2, to address these issues. We also carried out a similar analysis in an ACC cell line (H295R) in which IGF2 expression was knocked down with si- or shRNA. We found no significant differences in the clinical, biological and molecular (transcriptomic) traits between IGF2-high and IGF2-low ACC. The absence of IGF2 overexpression had little influence on the activation of tyrosine kinase pathways both in tumors and in H295 cells that express low levels of IGF2. In IGF2-low tumors, other growth factors (FGF9, PDGFA) are more expressed than in IGF2-high tumors, suggesting that they play a compensatory role in tumor progression. In addition, IGF2 knock-down in H295R cells substantially impaired growth (>50% inhibition), blocked cells in G1 phase, and promoted apoptosis (>2-fold). Finally, analysis of the 11p15 locus showed a paternal uniparental disomy in both IGF2-high and IGF2-low tumors, but low IGF2 expression could be explained in most IGF2-low ACC by an additional epigenetic modification at the 11p15 locus. Altogether, these observations confirm the active role of IGF2 in adrenocortical tumor growth, but also suggest that other growth promoting pathways may be involved in a subset of ACC with low IGF2 expression, which creates opportunities for the use of other targeted therapies.

Adrenocortical carcinomas (ACCs) are aggressive cancers originating in the cortex of the adrenal gland. Despite overall poor prognosis, ACC outcome is heterogeneous. We performed exome sequencing and SNP array analysis of 45 ACCs and identified recurrent alterations in known driver genes (CTNNB1, TP53, CDKN2A, RB1 and MEN1) and in genes not previously reported in ACC (ZNRF3, DAXX, TERT and MED12), which we validated in an independent cohort of 77 ACCs. ZNRF3, encoding a cell surface E3 ubiquitin ligase, was the most frequently altered gene (21%) and is a potential new tumor suppressor gene related to the β-catenin pathway. Our integrated genomic analyses further identified two distinct molecular subgroups with opposite outcome. The C1A group of ACCs with poor outcome displayed numerous mutations and DNA methylation alterations, whereas the C1B group of ACCs with good prognosis displayed specific deregulation of two microRNA clusters. Thus, aggressive and indolent ACCs correspond to two distinct molecular entities driven by different oncogenic alterations.

Context: Adrenocortical carcinoma (ACC) is a rare disease with a poor overall outcome. Transcriptome analysis identified two groups of ACCs with different prognosis. In aggressive ACCs, somatic mutations of the tumor suppressor gene TP53 and the proto-oncogene β-catenin are detected in 50% of cases. For the remaining aggressive ACCs and for the group with a better prognosis, molecular alterations are unknown., Objective: To identify new molecular actors driving adrenal tumorigenesis., Experimental Design: Analysis by mass array of 374 mutations among 32 common oncogenes or tumor suppressor genes was performed on the tumoral DNA of 26 ACCs, using Sequenom OncoCarta Panels., Results: Four mutations were identified, two previously known β-catenin mutations and one alteration in two other genes: JAK3 and retinoblastoma gene (RB1). The JAK3 alteration was found in leukocyte DNA and therefore considered as a polymorphism and not a somatic event. The full RB1 tumor suppressor gene was subsequently sequenced in a cohort of 49 ACCs (26 ACCs from the 'OncoCarta cohort' and 23 other ACCs): three somatic mutations were identified, all in the poor-outcome ACC group. By immunohistochemistry, a loss of the retinoblastoma protein (pRb) was found exclusively in aggressive ACCs in 27% of cases (seven out of 26), three of them with an inactivating RB1 mutation. Among the seven pRb-negative ACCs, five had an allele loss at the RB1 locus., Conclusions: Parallel analysis of somatic mutations among known cancer genes allowed us to identify RB1 as a new actor in aggressive ACCs. These results suggest a prognostic significance of pRb expression loss in ACCs.

Background: Wnt/β-catenin signaling pathway activation plays an important role in adrenocortical tumorigenesis, but is only in part related to β-catenin activating somatic mutations. Recently, genetic alteration in AXIN2, a key component of the Wnt/β-catenin signaling pathway, has been described in adrenocortical tumors and specifically in adrenocortical carcinoma (ACC)., Aim: To assess frequency and consequences of AXIN genes alteration on a large cohort of ACC., Patients and Methods: Forty-nine adult sporadic ACC, with expression data available, in addition to both ACC cell lines H295 and H295R were studied. AXIN2 exon 8 hot-spot sequencing was performed on the entire cohort. AXIN1 entire coding region was studied on the 8 ACC with nuclear β-catenin staining., Results: The previously described AXIN2 in-frame heterozygous 12bp deletion c2013&#95;2024del12 was found in 1 of the 49 ACC studied (2%), in a tumor with pSer45del activating CTNNB1 mutation and nuclear β-catenin staining. This heterozygous deletion was also found in the patient's germline DNA, extracted from peripheral blood leukocytes. This genetic alteration was also present in H295 and H295R cell lines. The single-nucleotide polymorphism rs35415678 was found with an allele frequency similar to those found in reference populations. No correlation between AXIN2 expression, AXIN2 genetic variant or nuclear β- catenin staining was observed. No AXIN1 alterations were found in the 8 ACC studied., Conclusions: AXIN genes do not play a major role in ACC tumorigenesis and Wnt/β-catenin signaling pathway activation. AXIN2 germline variant c2013&#95;2024del12 is likely to be a non-pathogenic polymorphism.

Context: Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and scant treatment options. In ACC, no personalized approach has emerged but no extensive molecular screening has been performed to date., Objective: The objective of the study was to evaluate the presence of a large number of potentially targetable molecular events in a large cohort of advanced ACC., Design, Setting, and Participants: We used hot spot gene sequencing (Ion Torrent, 40 patients) and comparative genomic hybridization (CGH; 28 patients; a subset of the entire cohort) in adult stage III-IV ACC samples to screen for mutations and copy number abnormalities of potential interest for therapeutic use in 46 and 130 genes, respectively., Results: At least one copy number alteration or mutation was found in 19 patients (47.5%). The most frequent mutations were detected on TP53, ATM, and CTNNB1 [6 of 40 (15%), 5 of 40 (12.5%), and 4 of 40 (10%), respectively]. The most frequent copy number alterations identified were: amplification of the CDK4 oncogene (5 of 28; 17.9%) and deletion of the CDKN2A (4 of 28; 14.3%) and CDKN2B (3 of 28; 10.7%) tumor suppressor genes. Amplifications of FGFR1, FGF9, or FRS2 were discovered in three subjects (10.7%). Associated alterations were: deletions of CDKN2A, CDKN2B with ATM mutations, and TP53 mutations with CTNNB1 mutations., Conclusions: No simple targetable molecular event emerged. Drugs targeting the cell cycle could be the most relevant new therapeutic approach for patients with advanced ACC. Inhibitors of the fibroblast growth factor receptor pathway could also be a therapeutic option in a subset of patients, whereas other targeted therapies should be considered on a case-by-case basis.

Purpose: DNA methylation is a mechanism for gene expression silencing in cancer. Limited information is available for adrenocortical tumors. Abnormal methylation at the IGF2/H19 locus is common in adrenocortical carcinomas. Our aim was to characterize the methylation in adrenocortical carcinomas at a whole-genome scale and to assess its clinical significance and its impact on gene expression., Experimental Design: Methylation patterns of CpG islands in promoter regions of 51 adrenocortical carcinomas and 84 adenomas were studied by the Infinium HumanMethylation27 Beadchip (Illumina, San Diego, CA). Methylation of 33 genes was studied by methylation-specific multiplex ligation-dependent probe amplification (MRC-Holland, Amsterdam, The Netherlands) in 15 carcinomas. Gene expression data were available for 87 tumors from a previous study (HG-U133Plus2.0 AffymetrixGeneChip; Affymetrix, Santa Clara, CA). Clinical information, including patient features and survival, were available for all tumors., Results: Methylation was higher in carcinomas than in adenomas (t test P = 3.1 × 10(-9)). Unsupervised clustering of DNA methylation profiles identified two groups of carcinomas, one with an elevated methylation level, evoking a CpG island methylator phenotype (CIMP). The subgroup of hypermethylated carcinomas was further divided in two subgroups, with different levels of methylation (CIMP-high and CIMP-low). This classification could be confirmed by methylation-specific multiplex ligation-dependent probe amplification. Hypermethylation was associated with a poor survival (Cox model P = 0.02). The transcriptome/methylation correlation showed 1741 genes (of 12,250) negatively correlated; among the top genes were H19 and other tumor suppressors (PLAGL-1, G0S2, and NDRG2)., Conclusions: This genome-wide methylation analysis reveals the existence of hypermethylated adrenocortical carcinomas, with a poorer prognosis. Hypermethylation in these tumors is important for silencing specific tumor suppressor genes.

Adrenocortical carcinoma (ACC) is a rare disease with an overall poor but heterogeneous prognosis. This heterogeneity could reflect different mechanisms of tumor development. Gene expression profiling by transcriptome analysis led to ACC being divided into two groups of tumors with very different outcomes. Somatic inactivating mutations of the tumor suppressor gene TP53 and activating mutations of the proto-oncogene β-catenin (CTNNB1) are the most frequent mutations identified in ACC. This study investigates the correlation between p53 and β-catenin alterations and the molecular classification of ACC by transcriptome analysis of 51 adult sporadic ACCs. All TP53 and CTNNB1 mutations seemed to be mutually exclusive and were observed only in the poor-outcome ACC group. Most of the abnormal p53 and β-catenin immunostaining was also found in this group. Fifty-two percent of the poor-outcome ACC group had TP53 or CTNNB1 mutations and 60% had abnormal p53 or β-catenin immunostaining. Unsupervised clustering transcriptome analysis of this poor-outcome group revealed three different subgroups, two of them being associated with p53 or β-catenin alterations, respectively. Analysis of p53 and β-catenin target gene expressions in each cluster confirmed a profound and anticipated effect on tumor biology, with distinct profiles logically associated with the respective pathway alterations. The third group had no p53 or β-catenin alteration, suggesting other unidentified molecular defects. This study shows the important respective roles of p53 and β-catenin in ACC development, delineating subgroups of ACC with different tumorigenesis and outcomes., (©2010 AACR.)