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Discovery Medicine Jan 2016Within the category of orphan diseases and rare malignancies, adrenocortical carcinoma (ACC) represents an aggressive entity with high mortality and morbidity. While... (Review)
Review
Within the category of orphan diseases and rare malignancies, adrenocortical carcinoma (ACC) represents an aggressive entity with high mortality and morbidity. While localized tumors which are diagnosed early can be cured with surgical intervention, there are prognostic factors which predict for micrometastases and consequent recurrent and advanced disease. In such cases, cytotoxic chemotherapy and mitotane have been utilized with a very modest degree of benefit. The poor prognosis of recurrent and advanced ACC has underscored the interest in nuanced characterization of ACC cases using next-generation sequencing (NGS)-based genomic and other '-omic' profiling to guide the precision medicine approach and personalized use of targeted and novel therapies.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Delivery of Health Care; Humans; Models, Biological
PubMed: 26896602
DOI: No ID Found -
The American Journal of Case Reports Apr 2021BACKGROUND Adrenocortical carcinomas are rare and aggressive tumors often diagnosed as incidentalomas. The malignancy can present with abnormal hormone secretion or the...
BACKGROUND Adrenocortical carcinomas are rare and aggressive tumors often diagnosed as incidentalomas. The malignancy can present with abnormal hormone secretion or the tumor may be non-functioning and present as a palpable mass causing discomfort. Here, we present a case of an adrenal cortical carcinoma originally identified as an incidentaloma. CASE REPORT A 63-year-old woman presented with abdominal pain and discomfort. A large abdominal mass, occupying the left upper and lower quadrant, was palpated. Imaging revealed a mass occupying the left abdomen between the stomach and the spleen, applying pressure on the pylorus, duodenum, splenic vessels, and pancreas. The mass size was 21.2×13×14.6 cm. Hormonal investigations were normal. Surgical exploration was performed, and the tumor was excised. Pathological analysis revealed an adrenocortical carcinoma and the patient underwent adjuvant chemotherapy. Twelve months later, the carcinoma recurred. The patient underwent a second operation in which the recurrent mass was excised along with the tail of the pancreas and a small part of the left lobe of the liver. The postoperative period was uneventful, and the patient was discharged home on the 7th postoperative day. No further adjuvant therapy was applied. The patient remains disease-free 18 months after the reoperation. CONCLUSIONS Giant adrenocortical carcinomas, although rare, pose a challenge to the surgical team both diagnostically and therapeutically. Surgical excision with the appropriate oncologic support can guarantee excellent outcomes.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Combined Modality Therapy; Female; Humans; Liver; Middle Aged; Neoplasm Recurrence, Local
PubMed: 33813589
DOI: 10.12659/AJCR.928875 -
Experimental and Clinical Endocrinology... Feb 2019Adrenocortical carcinoma is a rare endocrine malignant disease with a generally unfavorable but heterogeneous prognosis. Although even in advanced stages a subset of... (Review)
Review
Adrenocortical carcinoma is a rare endocrine malignant disease with a generally unfavorable but heterogeneous prognosis. Although even in advanced stages a subset of patients experiences long-term disease stabilisation, effective systemic treatment options are limited. Mitotane is the only approved drug and the combination of etoposide, doxorubicin and cisplatin (plus mitotane) is currently considered as treatment standard for advanced adrenocortical carcinoma based on the results of a large randomized phase III trial. However, progression-free survival is often limited and further treatment options are frequently needed. Here we summarize the current knowledge about second and third-line therapeutic modalities (local and systemic) in advanced disease. Following the recent ESE-ENSAT guidelines local therapies play an important role for these patients. Regarding systemic therapies the best data are available for gemcitabine+capecitabine or streptozotocin (both with or without mitotane). Furthermore, we introduce our own approach to patients with advanced adrenocortical carcinoma based on our experience as a large multidisciplinary clinic dedicated to the care of patients with this orphan disease.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Humans
PubMed: 30469158
DOI: 10.1055/a-0715-1946 -
European Journal of Endocrinology Apr 2022Molecular classification is important for the diagnosis and prognosis of adrenocortical tumors (ACT). Transcriptome profiles separate adrenocortical adenomas 'C2' from...
DESIGN
Molecular classification is important for the diagnosis and prognosis of adrenocortical tumors (ACT). Transcriptome profiles separate adrenocortical adenomas 'C2' from carcinomas, and identify two groups of carcinomas 'C1A' and 'C1B', of poor and better prognosis respectively. However, many ACT cannot be profiled because of improper or absent freezing procedures, a mandatory requirement so far. The main aim was to determine transcriptome profiles on formalin-fixed paraffin-embedded (FFPE) samples, using the new 3'-end RNA-sequencing technology. A secondary aim was to demonstrate the ability of this technique to explore large FFPE archives, by focusing on the rare oncocytic ACT variants.
METHODS
We included 131 ACT: a training cohort from Cochin hospital and an independent validation cohort from Wuerzburg hospital. The 3' transcriptome was generated from FFPE samples using QuantSeq (Lexogen, Vienna, Austria) and NextSeq500 (Illumina, San Diego, CA, USA).
RESULTS
In the training cohort, unsupervised clustering identified three groups: 'C1A' aggressive carcinomas (n = 28, 29%), 'C1B' more indolent carcinomas (n = 28, 29%), and 'C2' adenomas (n = 39, 41%). The prognostic value of FFPE transcriptome was confirmed in the validation cohort (5-year OS: 26% in 'C1A' (n = 26) and 100% in 'C1B' (n = 10), P = 0.003). FFPE transcriptome was an independent prognostic factor in a multivariable model including tumor stage and Ki-67 (OS HR: 7.5, P = 0.01). Oncocytic ACT (n = 19) did not form any specific cluster. Oncocytic carcinomas (n = 6) and oncocytic ACT of uncertain malignant potential (n = 4) were all in 'C1B'.
CONCLUSIONS
The 3' RNA-sequencing represents a convenient solution for determining ACT molecular class from FFPE samples. This technique should facilitate routine use and large retrospective studies.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Formaldehyde; Gene Expression Profiling; Humans; Paraffin; Paraffin Embedding; Prognosis; RNA; Retrospective Studies; Tissue Fixation; Transcriptome
PubMed: 35266879
DOI: 10.1530/EJE-21-1228 -
Endocrine Reviews Nov 2022The adrenal glands are paired endocrine organs that produce steroid hormones and catecholamines required for life. Adrenocortical carcinoma (ACC) is a rare and often...
The adrenal glands are paired endocrine organs that produce steroid hormones and catecholamines required for life. Adrenocortical carcinoma (ACC) is a rare and often fatal cancer of the peripheral domain of the gland, the adrenal cortex. Recent research in adrenal development, homeostasis, and disease have refined our understanding of the cellular and molecular programs controlling cortical growth and renewal, uncovering crucial clues into how physiologic programs are hijacked in early and late stages of malignant neoplasia. Alongside these studies, genome-wide approaches to examine adrenocortical tumors have transformed our understanding of ACC biology, and revealed that ACC is composed of distinct molecular subtypes associated with favorable, intermediate, and dismal clinical outcomes. The homogeneous transcriptional and epigenetic programs prevailing in each ACC subtype suggest likely susceptibility to any of a plethora of existing and novel targeted agents, with the caveat that therapeutic response may ultimately be limited by cancer cell plasticity. Despite enormous biomedical research advances in the last decade, the only potentially curative therapy for ACC to date is primary surgical resection, and up to 75% of patients will develop metastatic disease refractory to standard-of-care adjuvant mitotane and cytotoxic chemotherapy. A comprehensive, integrated, and current bench-to-bedside understanding of our field's investigations into adrenocortical physiology and neoplasia is crucial to developing novel clinical tools and approaches to equip the one-in-a-million patient fighting this devastating disease.
Topics: Humans; Adrenocortical Carcinoma; Adrenal Cortex Neoplasms; Mitotane; Adrenal Glands; Genomics
PubMed: 35551369
DOI: 10.1210/endrev/bnac012 -
Endokrynologia Polska 2016Adrenocortical carcinoma is associated with a low cure rate and a high recurrence rate. The prognosis is poor, and at diagnosis 30-40% of cases are already metastatic.... (Review)
Review
Adrenocortical carcinoma is associated with a low cure rate and a high recurrence rate. The prognosis is poor, and at diagnosis 30-40% of cases are already metastatic. The current therapeutic options (surgical resection, followed by adjuvant mitotane treatment +/- chemotherapy) are limited, and the results remain unsatisfactory. Key molecular events that contribute to formation of adrenocortical cancer are IGF2 overexpression, TP53-inactivating mutations, and constitutive activation of the Wnt/b-catenin signalling pathway via activating mutations of the b-catenin gene. The underlying genetic causes of inherited tumour syndromes have provided insights into molecular pathogenesis. The increased occurrence of adrenocortical tumours in Li-Fraumeni and Beckwith-Wiedemann syndromes, and Carney complex, has highlighted the roles of specific susceptibility genes: TP53, IGF2, and PRKAR1A, respectively. Further studies have confirmed that these genes are also involved in sporadic tumour cases. Crucially, transcriptome-wide studies have determined the differences between malignant and benign adrenocortical tumours, providing potential diagnostic tools. In conclusion, enhancing our understanding of the molecular events of adrenocortical tumourigenesis, especially with regard to the signalling pathways that may be disrupted, will greatly contribute to improving a range of available diagnostic, prognostic, and treatment approaches. (Endokrynol Pol 2016; 67 (4): 427-440).
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mutation; Signal Transduction
PubMed: 27387247
DOI: 10.5603/EP.a2016.0054 -
Frontiers in Endocrinology 2023Adrenocortical carcinomas are extremely rare in the paediatric population. Most of them are hormone-secretive lesions; therefore, they should be taken into consideration... (Review)
Review
Adrenocortical carcinomas are extremely rare in the paediatric population. Most of them are hormone-secretive lesions; therefore, they should be taken into consideration in a child with signs of precocious puberty and/or Cushing's syndrome symptoms. Nonetheless, differentiation from benign adrenal tumours is necessary. We report a rare case of adrenocortical carcinoma in a girl and a literature review using the PubMed database. A four-year-old girl presented with rapidly progressing precocious puberty and signs of Cushing's syndrome. Imaging of the abdomen revealed a large heterogeneous solid mass. Histopathologic evaluation confirmed adrenocortical carcinoma with high mitotic activity, atypical mitoses, pleomorphism, necrosis, and vascular invasion. After tumourectomy, a decrease of previously elevated hormonal blood parameters was observed. Genetic tests confirmed Li Fraumeni syndrome. Adrenocortical carcinoma should be suspected in children with premature pubarche and signs of Cushing's syndrome. Diagnosis must be based on clinical presentation, hormonal tests, imaging, and histopathological evaluation. Complete surgical resection of the tumour is the gold standard. Oncological treatment in children is not yet well-studied and should be individually considered, especially in advanced, inoperable carcinomas with metastases. Genetic investigations are useful for determining the prognosis in patients and their siblings.
Topics: Child, Preschool; Female; Humans; Adrenal Cortex Neoplasms; Adrenal Gland Neoplasms; Adrenocortical Carcinoma; Cushing Syndrome; Puberty, Precocious
PubMed: 38075063
DOI: 10.3389/fendo.2023.1216501 -
The Lancet. Diabetes & Endocrinology Oct 2023Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of... (Randomized Controlled Trial)
Randomized Controlled Trial Observational Study
Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study.
BACKGROUND
Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence.
METHODS
ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete.
FINDINGS
Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30-1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths.
INTERPRETATION
Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment.
FUNDING
AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health.
Topics: Humans; Mitotane; Adrenocortical Carcinoma; Disease-Free Survival; Adrenal Cortex Neoplasms
PubMed: 37619579
DOI: 10.1016/S2213-8587(23)00193-6 -
Current Opinion in Endocrinology,... Jun 2014Description of novel findings about the mechanism of action of mitotane and its activity as an adjunctive postoperative measure, or for treatment of advanced... (Review)
Review
PURPOSE OF REVIEW
Description of novel findings about the mechanism of action of mitotane and its activity as an adjunctive postoperative measure, or for treatment of advanced adrenocortical carcinoma.
RECENT FINDINGS
Several in-vitro studies have shown that mitotane suppresses gene transcription of different enzymatic steps of the steroidogenetic pathway. Moreover, mitotane induces CYP3A4 expression, thus accelerating the metabolic clearance of a variety of drugs including steroids. Retrospective studies provided evidence that adjunctive mitotane can prolong recurrence-free survival of treated patients. The concept of a therapeutic window of mitotane plasma concentrations was confirmed also for adjunctive treatment, but the relationship between mitotane concentration and given dose is loose. Genetic variability of the P450-dependent enzymes metabolizing mitotane may explain individual differences.
SUMMARY
Mitotane concentration of 14-20 mg/l should be reached and maintained during treatment also in an adjunctive setting. In advanced adrenocortical carcinoma, a high-dose starting regimen should be employed when mitotane is used as monotherapy. The combination of mitotane with other drugs should consider the possibility of pharmacologic interactions due to mitotane-induced activation of drug metabolism. This concept applies also to steroid replacement in mitotane-treated patients, who need higher doses to adjust for increased steroid metabolism.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Male; Mitotane; Neoplasm Recurrence, Local; Treatment Outcome
PubMed: 24732405
DOI: 10.1097/MED.0000000000000056 -
Current Opinion in Endocrinology,... Jun 2020The aim of this review is to summarize recent advances on development of in vivo preclinical models of adrenocortical carcinoma (ACC). (Review)
Review
PURPOSE OF REVIEW
The aim of this review is to summarize recent advances on development of in vivo preclinical models of adrenocortical carcinoma (ACC).
RECENT FINDINGS
Significant progress has been achieved in the underlying molecular mechanisms of adrenocortical tumorigenesis over the last decade, and recent comprehensive profiling analysis of ACC tumors identified several genetic and molecular drivers of this disease. Therapeutic breakthroughs, however, have been limited because of the lack of preclinical models recapitulating the molecular features and heterogeneity of the tumors. Recent publications on genetically engineered mouse models and development of patient-derived ACC xenografts in both nude mice and humanized mice now provide researchers with novel tools to explore therapeutic targets in the context of heterogeneity and tumor microenvironment in human ACC.
SUMMARY
We review current in-vivo models of ACC and discuss potential therapeutic opportunities that have emerged from these studies.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Animals; Cell Transformation, Neoplastic; Disease Models, Animal; Drug Screening Assays, Antitumor; Humans; Mice; Mice, Nude; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 32304391
DOI: 10.1097/MED.0000000000000543