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European Journal of Endocrinology Oct 2018Adrenocortical carcinoma (ACC) is a rare and in most cases steroid hormone-producing tumor with variable prognosis. The purpose of these guidelines is to provide...
European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors.
Adrenocortical carcinoma (ACC) is a rare and in most cases steroid hormone-producing tumor with variable prognosis. The purpose of these guidelines is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with ACC based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions, which we judged as particularly important for the management of ACC patients and performed systematic literature searches: (A) What is needed to diagnose an ACC by histopathology? (B) Which are the best prognostic markers in ACC? (C) Is adjuvant therapy able to prevent recurrent disease or reduce mortality after radical resection? (D) What is the best treatment option for macroscopically incompletely resected, recurrent or metastatic disease? Other relevant questions were discussed within the group. Selected Recommendations: (i) We recommend that all patients with suspected and proven ACC are discussed in a multidisciplinary expert team meeting. (ii) We recommend that every patient with (suspected) ACC should undergo careful clinical assessment, detailed endocrine work-up to identify autonomous hormone excess and adrenal-focused imaging. (iii) We recommend that adrenal surgery for (suspected) ACC should be performed only by surgeons experienced in adrenal and oncological surgery aiming at a complete en bloc resection (including resection of oligo-metastatic disease). (iv) We suggest that all suspected ACC should be reviewed by an expert adrenal pathologist using the Weiss score and providing Ki67 index. (v) We suggest adjuvant mitotane treatment in patients after radical surgery that have a perceived high risk of recurrence (ENSAT stage III, or R1 resection, or Ki67 >10%). (vi) For advanced ACC not amenable to complete surgical resection, local therapeutic measures (e.g. radiation therapy, radiofrequency ablation, chemoembolization) are of particular value. However, we suggest against the routine use of adrenal surgery in case of widespread metastatic disease. In these patients, we recommend either mitotane monotherapy or mitotane, etoposide, doxorubicin and cisplatin depending on prognostic parameters. In selected patients with a good response, surgery may be subsequently considered. (vii) In patients with recurrent disease and a disease-free interval of at least 12 months, in whom a complete resection/ablation seems feasible, we recommend surgery or alternatively other local therapies. Furthermore, we offer detailed recommendations about the management of mitotane treatment and other supportive therapies. Finally, we suggest directions for future research.
Topics: Adrenal Cortex Neoplasms; Adrenalectomy; Adrenocortical Carcinoma; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Catheter Ablation; Chemoembolization, Therapeutic; Cisplatin; Disease Management; Doxorubicin; Endocrinology; Etoposide; Europe; Humans; Mitotane; Neoplasm Metastasis; Prognosis; Radiotherapy; Societies, Medical
PubMed: 30299884
DOI: 10.1530/EJE-18-0608 -
Frontiers in Endocrinology 2022Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal gland with an unfavorable prognosis. It is rare in the pediatric population, with an... (Review)
Review
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal gland with an unfavorable prognosis. It is rare in the pediatric population, with an incidence of 0.2-0.3 patients per million in patients under 20 years old. It is primarily associated with Li-Fraumeni and Beckwith-Wiedemann tumor predisposition syndromes in children. The incidence of pediatric ACC is 10-15fold higher in southern Brazil due to a higher prevalence of mutation associated with Li-Fraumeni syndrome in that population. Current treatment protocols are derived from adult ACC and consist of surgery and/or chemotherapy with etoposide, doxorubicin, and cisplatin (EDP) with mitotane. Limited research has been reported on other treatment modalities for pediatric ACC, including mitotane, pembrolizumab, cabozantinib, and chimeric antigen receptor autologous cell (CAR-T) therapy.
Topics: Adult; Humans; Child; Young Adult; Adrenocortical Carcinoma; Mitotane; Adrenal Cortex Neoplasms; Li-Fraumeni Syndrome
PubMed: 36387865
DOI: 10.3389/fendo.2022.961650 -
Best Practice & Research. Clinical... May 2020Adrenocortical carcinoma (ACC) is an aggressive cancer characterized by poor survival. Apart from radical surgery, there is a limited range of therapeutic options and... (Review)
Review
Adrenocortical carcinoma (ACC) is an aggressive cancer characterized by poor survival. Apart from radical surgery, there is a limited range of therapeutic options and mitotane remains the cornerstone of medical treatment of ACC in either adjuvant or palliative settings. The aim of adjuvant mitotane therapy is to reduce the risk of ACC recurrence following surgical removal of the tumor. Use of mitotane in an adjuvant setting is off-label, but the recent guidelines endorsed by the European Society of Endocrinology (ESE) and the European Network for the Study of Adrenal Tumors (ENSAT) recommend it in ACC patients at high risk of recurrence. The palliative use of mitotane for treatment of advanced ACC aims at controlling tumor progression and, when present, hormone secretion. In this clinical setting, mitotane is used in association with chemotherapy to treat the more aggressive forms, while mitotane monotherapy is reserved for less progressive ACC. Many years after its introduction in clinical practice, there are still uncertainties surrounding the use of this old drug and the derived benefits. Moreover, physicians who use mitotane should recognize and manage the systemic effects of the drug that need a complex supporting therapy.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Endocrinology; Humans; Mitotane
PubMed: 32179008
DOI: 10.1016/j.beem.2020.101415 -
Veterinary Medicine (Auckland, N.Z.) 2018Hypoadrenocorticism (HOAC; Addison's disease) is an endocrine condition seen in small animal practice. Dogs with this disease can present in a variety of ways from acute... (Review)
Review
Hypoadrenocorticism (HOAC; Addison's disease) is an endocrine condition seen in small animal practice. Dogs with this disease can present in a variety of ways from acute hypovolemic collapse to vague, chronic, waxing, and waning clinical signs. In the most common form of this disease, animals have both mineralocorticoid and glucocorticoid deficiency, resulting in hyponatremia and hyperkalemia, and signs of cortisol deficiency. The etiology may be immune-mediated destruction of the adrenal cortex, drug-induced adrenocortical necrosis (mitotane), enzyme inhibition (trilostane), or infiltrative processes such as neoplastic or fungal disease. Much less commonly, dogs have signs of cortisol deficiency, but no electrolyte changes. This is referred to as atypical HOAC. The veterinarian needs to have a clinical suspicion for HOAC to make a diagnosis in a timely manner. Treatment of dogs with an acute presentation prioritizes correcting the hypovolemia, hyperkalemia, acidosis, and hypoglycemia. Fluid therapy addresses most of these issues, but other directed therapies may be required in the most severe cases. For chronic management, all patients with Addison's disease will require replacement of glucocorticoids (usually prednisone), and most patients require replacement of mineralocorticoids with either desoxycorticosterone pivalate or fludrocortisone. Atypical Addisonians do not require mineralocorticoid supplementation, but electrolytes should be monitored in case the need arises in the future. The prognosis for dogs treated for HOAC promptly and appropriately is excellent; most patients die from other diseases. However, if the diagnosis is missed, patients may die as a consequence of HOAC. Thus, knowledge of the hallmarks of Addison's disease is imperative.
PubMed: 30050862
DOI: 10.2147/VMRR.S125617 -
Endocrine Practice : Official Journal... Nov 2020The aim of this Disease State Clinical Review is to provide a practical approach to patients with newly diagnosed adrenocortical carcinoma, as well as to follow-up and... (Review)
Review
American Association of Clinical Endocrinology Disease State Clinical Review on the Evaluation and Management of Adrenocortical Carcinoma in an Adult: a Practical Approach.
OBJECTIVE
The aim of this Disease State Clinical Review is to provide a practical approach to patients with newly diagnosed adrenocortical carcinoma, as well as to follow-up and management of patients with persistent or recurrent disease.
METHODS
This is a case-based clinical review. The provided recommendations are based on evidence available from randomized prospective clinical studies, cohort studies, cross-sectional and case-based studies, and expert opinions.
RESULTS
Adrenocortical carcinoma is a rare malignancy, often with poor outcomes. For any patient with an adrenal mass suspicious for adrenocortical carcinoma, the approach should include prompt evaluation with detailed history and physical exam, imaging, and biochemical adrenal hormone assessment. In addition to adrenal-focused imaging, patients should be evaluated with chest-abdomen-pelvis cross-sectional imaging to define the initial therapy plan. Patients with potentially resectable disease limited to the adrenal gland should undergo en bloc open surgery by an expert surgeon. For patients presenting with advanced or recurrent disease, a multidisciplinary approach considering curative repeat surgery, local control with surgery, radiation therapy or radiofrequency ablation, or systemic therapy with mitotane and/or cytotoxic chemotherapy is recommended.
CONCLUSION
As most health care providers will rarely encounter a patient with adrenocortical carcinoma, we recommend that patients with suspected adrenocortical carcinoma be evaluated by an expert multidisciplinary team which includes clinicians with expertise in adrenal tumors, including endocrinologists, oncologists, surgeons, radiation oncologists, pathologists, geneticists, and radiologists. We recommend that patients in remote locations be followed by the local health care provider in collaboration with a multidisciplinary team at an expert adrenal tumor program.
ABBREVIATIONS
ACC = adrenocortical carcinoma; ACTH = adrenocorticotropic hormone; BRACC = borderline resectable adrenocortical carcinoma; CT = computed tomography; DHEAS = dehydroepiandrosterone sulfate; EDP = etoposide, doxorubicin, cisplatin; FDG = F-fluorodeoxyglucose; FNA = fine-needle aspiration; HU = Hounsfield units; IVC = inferior vena cava; LFS = Li-Fraumeni syndrome; MEN1 = multiple endocrine neoplasia type 1; MRI = magnetic resonance imaging; OAC = oncocytic adrenocortical carcinoma; PC = palliative care; PET = positron emission tomography.
Topics: Adrenal Cortex Neoplasms; Adrenal Gland Neoplasms; Adrenocortical Carcinoma; Adult; Humans; Mitotane; Prospective Studies; United States
PubMed: 33875173
DOI: 10.4158/DSCR-2020-0567 -
Journal of Translational Medicine Oct 2022Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized...
BACKGROUND
Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate.
METHODS
By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism.
RESULTS
Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way.
CONCLUSIONS
CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Animals; Apoptosis; Aurora Kinase A; CDC2 Protein Kinase; Cell Division; Cell Line, Tumor; Cell Proliferation; Epithelial-Mesenchymal Transition; Humans; Mice; Mice, Nude; Mitotane; Necroptosis; Pyroptosis; RNA-Binding Proteins
PubMed: 36184616
DOI: 10.1186/s12967-022-03641-y -
Radiology Case Reports Jun 2021Adrenocortical carcinoma (ACC) is a rare malignancy that arises from the adrenal cortex and can be classified as either non-functioning or functioning. A patient with...
Adrenocortical carcinoma (ACC) is a rare malignancy that arises from the adrenal cortex and can be classified as either non-functioning or functioning. A patient with non-functioning ACC may present no specific symptoms. Imaging analysis can provide some information to a clinician who suspects ACC, such as tumor size, density, washout, necrosis, hemorrhage, and calcification. Histopathology is used to confirm and determine the origin of the malignancy and can provide relevant prognostic information. Microscopic findings can be used to obtain information such as the Weiss score, resection surface features, Ki-67 proliferative index, and the degree of capsular and vascular invasion. Surgery can be curative for localized tumors, and adjuvant therapy using mitotane and cytotoxic chemotherapy is often employed for advanced-stage tumors. We describe a case report of a 32-year-old man with a non-functioning ACC that highlights the importance of radiological and pathological features in the diagnosis of ACC and their use as prognostic factors.
PubMed: 33889224
DOI: 10.1016/j.radcr.2021.03.006 -
Proceedings of the National Academy of... May 2023Iridoviridae, such as the lymphocystis disease virus-1 (LCDV-1) and other viruses, encode viral insulin-like peptides (VILPs) which are capable of triggering insulin...
Iridoviridae, such as the lymphocystis disease virus-1 (LCDV-1) and other viruses, encode viral insulin-like peptides (VILPs) which are capable of triggering insulin receptors (IRs) and insulin-like growth factor receptors. The homology of VILPs includes highly conserved disulfide bridges. However, the binding affinities to IRs were reported to be 200- to 500-fold less effective compared to the endogenous ligands. We therefore speculated that these peptides also have noninsulin functions. Here, we report that the LCDV-1 VILP can function as a potent and highly specific inhibitor of ferroptosis. Induction of cell death by the ferroptosis inducers erastin, RSL3, FIN56, and FINO2 and nonferroptotic necrosis produced by the thioredoxin-reductase inhibitor ferroptocide were potently prevented by LCDV-1, while human insulin had no effect. Fas-induced apoptosis, necroptosis, mitotane-induced cell death and growth hormone-releasing hormone antagonist-induced necrosis were unaffected, suggesting the specificity to ferroptosis inhibition by the LCDV-1 VILP. Mechanistically, we identified the viral C-peptide to be required for inhibition of lipid peroxidation and ferroptosis inhibition, while the human C-peptide exhibited no antiferroptotic properties. In addition, the deletion of the viral C-peptide abolishes radical trapping activity in cell-free systems. We conclude that iridoviridae, through the expression of insulin-like viral peptides, are capable of preventing ferroptosis. In analogy to the viral mitochondrial inhibitor of apoptosis and the viral inhibitor of RIP activation (vIRA) that prevents necroptosis, we rename the LCDV-1 VILP a viral peptide inhibitor of ferroptosis-1. Finally, our findings indicate that ferroptosis may function as a viral defense mechanism in lower organisms.
Topics: Humans; Insulin; C-Peptide; Apoptosis; Necrosis; Cell Death
PubMed: 37186845
DOI: 10.1073/pnas.2300320120 -
Journal of Physiology and Pharmacology... Feb 2017Adrenocortical carcinoma is a rare disease with poor prognosis. Mitotane is the most effective agent in post-operative treatment (or when inoperable). It selectively... (Review)
Review
Adrenocortical carcinoma is a rare disease with poor prognosis. Mitotane is the most effective agent in post-operative treatment (or when inoperable). It selectively limits growth and bioactivity of adrenal tissue. Despite 60 years of use, the basis for its action has yet to be convincingly established. This review summarizes current knowledge of mitotane effects, based on studies on adrenal tissue and primary cell cultures, with emphasis on more recent studies of cell lines. We consider features of the adrenal cortex that might explain mitotane selectivity, and review effects on non-adrenal cells. Since the most clear-cut mitotane effects have been observed for mitochondria, this topic is the core of the review. Mitochondria present unique characteristics in steroidogenic tissue and are known to be important in malignancy development and apoptosis. We look at the evidence for mitotane activation within mitochondria, its impact on mitochondrial energy metabolism and other cellular processes as well as on downstream effects in the cell, such as apoptosis initiation. Further genomic and proteomic investigative studies are likely to yield useful results.
Topics: Adrenal Cortex; Adrenocortical Carcinoma; Animals; Antineoplastic Agents, Hormonal; Apoptosis; Cell Death; Humans; Mitochondria; Mitotane; Proteins; Proteome; Steroids
PubMed: 28456766
DOI: No ID Found