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The Journal of Clinical Endocrinology... Mar 2022Adrenocortical carcinoma (ACC) is a rare endocrine malignancy that affects patients across the age spectrum. Although the overall survival in patients with ACC is poor,... (Review)
Review
CONTEXT
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy that affects patients across the age spectrum. Although the overall survival in patients with ACC is poor, there is significant heterogeneity in terms of outcomes, presentation, and underlying genetic drivers.
EVIDENCE ACQUISITION
This review is based on the evidence collected from primary research studies, expert reviews, and published guidelines. The studies were identified through PubMed search with key words "adrenocortical carcinoma," "prognosis," "pathology," and "genetics." The PubMed search was complemented by authors' expertise, research, and clinical experience in the field of ACC.
EVIDENCE SYNTHESIS
Identification of biomarkers has been critical to gain better insight into tumor behavior and to guide therapeutic approach to patients. Tumor stage, resection status, and Ki67 are pathological tumor characteristics that have been identified as prognosticators in patients with ACC. Cortisol excess also correlates with worse prognosis. Clinical and histopathological characteristics help stratify patient outcomes, yet still up to 25% of patients have a different outcome than predicted. To bridge this gap, comprehensive genomic profiling studies have characterized additional profiles that correlate with clinical outcomes. In addition, studies of clinically applicable molecular markers are under way to further stratify outcomes in patients with ACC tumors.
CONCLUSIONS
Clinical predictors in combination with pathological markers play a critical role in the approach to patients with ACC. Recent advances in genetic prognosticators will help extend the stratification of these tumors and contribute to a personalized therapeutic approach to patients with ACC.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Humans; Prognosis
PubMed: 34850906
DOI: 10.1210/clinem/dgab866 -
British Journal of Clinical Pharmacology Jul 2021Mitotane is the only adrenolytic drug approved by the Food and Drug Administration for treating adrenocortical carcinoma (ACC). This drug has cytotoxic effects on tumour... (Review)
Review
Mitotane is the only adrenolytic drug approved by the Food and Drug Administration for treating adrenocortical carcinoma (ACC). This drug has cytotoxic effects on tumour tissues; it induces cell death and antisecretory effects on adrenal cells by inhibiting the synthesis of adrenocortical steroids, which are involved in the pathogenesis of ACC. However, high doses of mitotane are usually necessary to reach the therapeutic plasma concentration, which may result in several adverse effects. This suggests that important pharmacological processes, such as first pass metabolism, tissue accumulation and extensive time for drug elimination, are associated with mitotane administration. Few studies have reported the pharmacological aspects and therapeutic effects of mitotane. Therefore, the aim of this review was to summarize the chemistry, pharmacokinetics and pharmacodynamics, and therapeutic and toxic effects of mitotane. This review also discusses new perspectives of mitotane formulation that are currently under investigation. Understanding the pharmacological profile of mitotane can improve the monitoring and efficacy of this drug in ACC treatment and can provide useful information for the development of new drugs with specific action against ACC with fewer adverse effects.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Humans; Mitotane; Steroids
PubMed: 33382119
DOI: 10.1111/bcp.14721 -
Frontiers in Endocrinology 2022Adrenal masses are one of the most common tumors in humans. The majority are benign and non-functioning and therefore do not require immediate treatment. In contrast,... (Review)
Review
Adrenal masses are one of the most common tumors in humans. The majority are benign and non-functioning and therefore do not require immediate treatment. In contrast, the rare adrenal malignant tumors are often highly aggressive and with poor prognosis. Besides usually being detected in advanced stages, often already with metastases, one of the reasons of the unfavorable outcome of the patients with adrenal cancer is the absence of effective treatments. Autophagy is one of the intracellular pathways targeted by several classes of chemotherapeutics. Mitotane, the most commonly used drug for the treatment of adrenocortical carcinoma, was recently shown to also modulate autophagy. Autophagy is a continuous programmed cellular process which culminates with the degradation of cellular organelles and proteins. However, being a dynamic mechanism, understanding the autophagic flux can be highly complex. The role of autophagy in cancer has been described paradoxically: initially described as a tumor pro-survival mechanism, different studies have been showing that it may result in other outcomes, namely in tumor cell death. In adrenal tumors, this dual role of autophagy has also been addressed in recent years. Studies reported both induction and inhibition of autophagy as a treatment strategy of adrenal malignancies. Importantly, most of these studies were performed using cell lines. Consequently clinical studies are still required. In this review, we describe what is known about the role of autophagy modulation in treatment of adrenal tumors. We will also highlight the aspects that need further evaluation to understand the paradoxical role of autophagy in adrenal tumors.
Topics: Adrenal Cortex Neoplasms; Adrenal Gland Neoplasms; Adrenocortical Carcinoma; Autophagy; Cell Death; Humans
PubMed: 35966083
DOI: 10.3389/fendo.2022.937367 -
Endocrinology, Diabetes & Metabolism Jul 2022Adrenocortical carcinoma (ACC) is a rare cancer with an annual incidence of 0.7-2 cases per million population and 5-year survival of 31.2%. Adrenal insufficiency (AI)... (Review)
Review
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare cancer with an annual incidence of 0.7-2 cases per million population and 5-year survival of 31.2%. Adrenal insufficiency (AI) is a common and life shortening complication of ACC, and little is understood about how it impacts on patients' experience.
OBJECTIVE
To understand patients' lived experience of the condition, its treatment, care process, impact of AI on ACC wellbeing, self-care needs and support.
METHODS
Systematic review of MEDLINE, EMBASES, CINAHL, PsycINFO and Open Grey for studies published until February 2021. All research designs were included. The findings underwent a thematic analysis and narrative synthesis. Studies quality was assessed using mixed method assessment tools.
RESULTS
A total of 2837 citations were identified; 15 titles with cohort, cross-sectional, case series and case report study designs met the inclusion criteria involving 479 participants with adrenal insufficiency secondary to adrenocortical carcinoma (AI/ACC). Quantitative research identified impacts of disease and treatment on survivorship, the burden of living with AI/ACC, toxicity of therapies, supporting self-care and AI management. These impact factors included adjuvant therapies involved and their toxicities, caregivers/family supports, healthcare and structure support in place, specialist skill and knowledge provided by healthcare professional on ACC management. No qualitative patient experiences evidence was identified.
CONCLUSION
ACC appears to have high impact on patients' wellbeing including the challenges with self-care and managing AI. Evidence is needed to understand patient experience from a qualitative perspective.
Topics: Adrenal Cortex Neoplasms; Adrenal Insufficiency; Adrenocortical Carcinoma; Caregivers; Cross-Sectional Studies; Humans
PubMed: 35670031
DOI: 10.1002/edm2.341 -
Turk Patoloji Dergisi 2015Adrenocortical carcinoma is generally considered a single entity by pathologists and clinicians. Nevertheless, the knowledge cumulated along the last decade on the... (Review)
Review
Adrenocortical carcinoma is generally considered a single entity by pathologists and clinicians. Nevertheless, the knowledge cumulated along the last decade on the pathological characterization, the clinical outcome and the molecular pathogenesis of adrenocortical carcinoma demonstrate that one of the most relevant emerging issues is related to its heterogeneity. Three major morphological variants have been described (oncocytic, myxoid and sarcomatoid) but are not included in the current WHO classification, yet. Moreover, even "conventional" adrenocortical carcinomas have a high degree of morphological heterogeneity as well as different mitotic/proliferative capacity, either among different cases or within individual lesions. Furthermore, immunohistochemical and molecular studies, based on a wide set of different methodologies, identified novel biomarkers in adrenocortical carcinoma of diagnostic and prognostic relevance, which claimed again the concept that this tumor type represents an heterogeneous group of neoplasms which cannot be considered a unique entity. The integration between morphology, immunophenotype and molecular data is expected in the next years to build a novel concept of adrenocortical carcinoma classification into specific subgroups, as it is currently approached for other types of neoplasms such as breast or lung cancer, which are not merely descriptive, but also characterized by a specific biological and clinical behavior.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Biomarkers, Tumor; Biopsy; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Molecular Diagnostic Techniques; Neoplasm Grading; Pathology, Molecular; Phenotype; Predictive Value of Tests
PubMed: 26177320
DOI: 10.5146/tjpath.2015.01317 -
The Netherlands Journal of Medicine Feb 2007Adrenocortical carcinoma is a rare disease with a poor prognosis. Patients can present with a hormonal syndrome or with general symptoms from an abdominal mass. The... (Review)
Review
Adrenocortical carcinoma is a rare disease with a poor prognosis. Patients can present with a hormonal syndrome or with general symptoms from an abdominal mass. The pathogenesis is unknown. Sometimes the adrenocortical carcinoma is associated with tumour syndromes such as the Beckwith-Wiedemann and Li-Fraumeni syndrome; however, most tumours are sporadic. Using one of the international classification methods, histopathological research can in almost all cases distinguish between adrenocortical adenoma and carcinoma. complete surgical resection is the treatment of choice for adrenocortical carcinoma. Mitotane is given when surgery is not possible, after incomplete resection or for metastatic disease. Frequently used chemotherapeutic combinations are etoposide, doxorubicin, cisplatin and mitotane (EDP/M) and streptozotocin and mitotane (SZ/M). International and national cooperation has resulted in a randomised trial aimed at determining a standard therapy in advanced adrenocortical carcinoma. The Dutch Adrenal Network is a national cooperation of endocrinologists, pathologists and oncologists from all eight academic centres and Máxima Medical centre. The network combines knowledge and expertise and gives patients the opportunity to receive optimal treatment in their own district.
Topics: Academic Medical Centers; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Doxorubicin; Etoposide; Humans; Internationality; Mitotane; Netherlands; Streptozocin
PubMed: 17379929
DOI: No ID Found -
Cells Nov 2022Adrenocortical carcinoma (ACC) is a malignancy of the endocrine system. We collected clinical and pathological features, genomic mutations, DNA methylation profiles, and...
Adrenocortical carcinoma (ACC) is a malignancy of the endocrine system. We collected clinical and pathological features, genomic mutations, DNA methylation profiles, and mRNA, lncRNA, microRNA, and somatic mutations in ACC patients from the TCGA, GSE19750, GSE33371, and GSE49278 cohorts. Based on the MOVICS algorithm, the patients were divided into ACC1-3 subtypes by comprehensive multi-omics data analysis. We found that immune-related pathways were more activated, and drug metabolism pathways were enriched in ACC1 subtype patients. Furthermore, ACC1 patients were sensitive to PD-1 immunotherapy and had the lowest sensitivity to chemotherapeutic drugs. Patients with the ACC2 subtype had the worst survival prognosis and the highest tumor-mutation rate. Meanwhile, cell-cycle-related pathways, amino-acid-synthesis pathways, and immunosuppressive cells were enriched in ACC2 patients. Steroid and cholesterol biosynthetic pathways were enriched in patients with the ACC3 subtype. DNA-repair-related pathways were enriched in subtypes ACC2 and ACC3. The sensitivity of the ACC2 subtype to cisplatin, doxorubicin, gemcitabine, and etoposide was better than that of the other two subtypes. For 5-fluorouracil, there was no significant difference in sensitivity to paclitaxel between the three groups. A comprehensive analysis of multi-omics data will provide new clues for the prognosis and treatment of patients with ACC.
Topics: Humans; Adrenocortical Carcinoma; Multiomics; Cisplatin; Adrenal Cortex Neoplasms; Data Analysis
PubMed: 36497046
DOI: 10.3390/cells11233784 -
Journal of Visceral Surgery Oct 2017Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. The presence of a mass syndrome or signs of hormonal hypersecretion often lead to its discovery,... (Review)
Review
Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. The presence of a mass syndrome or signs of hormonal hypersecretion often lead to its discovery, but more and more frequently, adrenocortical malignancy is fortuitously discovered as an incidentaloma. Cross-sectional imaging (CT and MRI) often points to the malignant character of the adrenal mass. Needle biopsy is contraindicated. Laboratory testing showing combined hypersecretion of cortisol, androgens or inactive corticosteroid precursors is highly suggestive of ACC. An 18F-fluoro-deoxyglucose Positron Emission Tomography (PET scan) should be performed to evaluate the malignancy of an adrenal mass and to detect regional or distant metastases. Although the majority of ACC are diagnosed at a locally advanced or metastatic stage, radical resection offers the only hope of cure. The peri-operative management of patients with ACC is not yet standardized. The aim of this review is to summarize the actual knowledge of the surgical management of ACC.
Topics: Adrenal Cortex Neoplasms; Adrenalectomy; Adrenocortical Carcinoma; Disease-Free Survival; Female; Humans; Laparoscopy; Laparotomy; Magnetic Resonance Imaging; Male; Neoplasm Invasiveness; Neoplasm Staging; Positron Emission Tomography Computed Tomography; Prognosis; Rare Diseases; Risk Assessment; Survival Analysis; Treatment Outcome
PubMed: 28754418
DOI: 10.1016/j.jviscsurg.2017.06.010 -
Molecular and Cellular Endocrinology Mar 2012The continuous centripetal repopulation of the adrenal cortex is consistent with a population of cells endowed with the stem/progenitor cell properties of self-renewal... (Review)
Review
The continuous centripetal repopulation of the adrenal cortex is consistent with a population of cells endowed with the stem/progenitor cell properties of self-renewal and pluripotency. The adrenocortical capsule and underlying undifferentiated cortical cells are emerging as critical components of the stem/progenitor cell niche. Recent genetic analysis has identified various signaling pathways including Sonic Hedgehog (Shh) and Wnt as crucial mediators of adrenocortical lineage and organ homeostasis. Shh expression is restricted to the peripheral cortical cells that express a paucity of steroidogenic genes but give rise to the underlying differentiated cells of the cortex. Wnt/β-catenin signaling maintains the undifferentiated state and adrenal fate of adrenocortical stem/progenitor cells, in part through induction of its target genes Dax1 and inhibin-α, respectively. The pathogenesis of ACC, a rare yet highly aggressive cancer with an extremely poor prognosis, is slowly emerging from studies of the stem/progenitor cells of the adrenal cortex coupled with the genetics of familial syndromes in which ACC occurs. The frequent observation of constitutive activation of Wnt signaling due to loss-of-function mutations in the tumor suppressor gene APC or gain-of-function mutation in β-catenin in both adenomas and carcinomas, suggests perhaps that the Wnt pathway serves an early or initiating insult in the oncogenic process. Loss of p53 might be predicted to cooperate with additional genetic insults such as IGF2 as both are the most common genetic abnormalities in malignant versus benign adrenocortical neoplasms. It is unclear whether other factors such as Pod1 and Pref1, which are implicated in stem/progenitor cell biology in the adrenal and/or other organs, are also implicated in the etiology of adrenocortical carcinoma. The rarity and heterogeneous presentation of ACC makes it difficult to identify the cellular origin and the molecular progression to cancer. A more complete understanding of adrenocortical stem/progenitor cell biology will invariably aid in characterization of the molecular details of ACC tumorigenesis and may offer new options for therapeutic intervention.
Topics: Adrenal Cortex; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Animals; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Humans; Mutation; Neoplasm Proteins; Neoplastic Stem Cells; Pluripotent Stem Cells; Wnt Signaling Pathway
PubMed: 22266195
DOI: 10.1016/j.mce.2011.12.006 -
Frontiers in Endocrinology 2023Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis. The disease originates from the cortex of adrenal gland and lacks effective treatment....
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis. The disease originates from the cortex of adrenal gland and lacks effective treatment. Efforts have been made to elucidate the pathogenesis of ACC, but the molecular mechanisms remain elusive. To identify key genes and pathways in ACC, the expression profiles of GSE12368, GSE90713 and GSE143383 were downloaded from the Gene Expression Omnibus (GEO) database. After screening differentially expressed genes (DEGs) in each microarray dataset on the basis of cut-off, we identified 206 DEGs, consisting of 72 up-regulated and 134 down-regulated genes in three datasets. Function enrichment analyses of DEGs were performed by DAVID online database and the results revealed that the DEGs were mainly enriched in cell cycle, cell cycle process, mitotic cell cycle, response to oxygen-containing compound, progesterone-mediated oocyte maturation, p53 signaling pathway. The STRING database was used to construct the protein-protein interaction (PPI) network, and modules analysis was performed using Cytoscape. Finally, we filtered out eight hub genes, including CDK1, CCNA2, CCNB1, TOP2A, MAD2L1, BIRC5, BUB1 and AURKA. Biological process analysis showed that these hub genes were significantly enriched in nuclear division, mitosis, M phase of mitotic cell cycle and cell cycle process. Violin plot, Kaplan-Meier curve and stage plot of these hub genes confirmed the reliability of the results. In conclusion, the results in this study provided reliable key genes and pathways for ACC, which will be useful for ACC mechanisms, diagnosis and candidate targeted treatment.
Topics: Humans; Gene Expression Profiling; Adrenocortical Carcinoma; Gene Regulatory Networks; Reproducibility of Results; Adrenal Cortex Neoplasms; Computational Biology
PubMed: 38053725
DOI: 10.3389/fendo.2023.1250033