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13 pages, 3034 KiB

Open AccessArticle

Re-Evaluation of Combinational Efficacy and Synergy of the Italian Protocol In Vitro: Are We Truly Optimizing Benefit or Permitting Unwanted Toxicity?

by Chitra Subramanian, Reid McCallister, Dawn Kuszynski and Mark S. Cohen

Biomedicines 2021, 9(9), 1190; https://doi.org/10.3390/biomedicines9091190 - 10 Sep 2021

Cited by 1 | Viewed by 1635

Abstract

Introduction: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, with very poor prognosis as a majority of the patients have advanced disease at the time of diagnosis. Currently, adjuvant therapy for most patients consists of either mitotane (M) alone or in combination with [...] Read more.

Introduction: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, with very poor prognosis as a majority of the patients have advanced disease at the time of diagnosis. Currently, adjuvant therapy for most patients consists of either mitotane (M) alone or in combination with multi-drug chemotherapeutics such as etoposide (E), doxorubicin (D), and cisplatin (P), known as the Italian protocol (IP; EDPM). This multi-drug treatment regimen, however, carries significant toxicity potential for patients. One way to improve toxicity profiles with these drugs in combination is to understand where their synergy occurs and over what dosing range so that lower dose regimens could be applied in combination with equal or improved efficacy. We hypothesize that a better understanding of the synergistic effects as well as the regulation of steroidogenic enzymes during combination therapy may provide more optimized combinational options with good potency and lower toxicity profiles. Methods: Two human ACC cell lines, NCI-H295R (hormonally active) and SW13 (hormonally inactive), were grown in 2D culture in appropriate growth medium. The viability of the cells after treatment with varying concentrations of the drugs (E, D, and P) either alone or in combinations with M was determined using the CellTiter Glow assay after 72 h, and the combination index for each was calculated using Compusyn by the Chou–Talalay method. The expression levels of enzymes associated with steroidogenesis were evaluated by RT-PCR in NCI-H295R. Results: When both cell lines were treated with M (ranging 25–50 μM), +E (ranging 18.75–75 μM), and +D (ranging 0.625–2.5 μM) we observed a synergistic effect (CI < 1) with potency equivalent to the full Italian protocol (IP), whereas combining M + P + D had an antagonistic effect (CI > 1) indicating the negative effect of adding cisplatin in the combination. Comparing the hormonally active and inactive cell lines, M + P + E was antagonistic in NCI-H295R and synergistic in SW13. Treatment of NCI-H295R cells with antagonistic combinations (M + P + D, M + P + E) resulted in a significant decrease in the levels of steroidogenic enzymes STAR, CYP11A1, and CYP21A2 compared to IP (p < 0.05) while M + E + D resulted in increased expression or no significant effect compared to IP across all genes tested. Conclusions: The synergistic effect for M + E + D was significant and equivalent in potency to the full IP in both cell lines and resulted in a steroidogenic gene expression profile similar to or better than that of full IP, warranting further evaluation. Future in vivo evaluation of the combination of M + E + D (with removal of P from the IP regimen) may lower toxicity while maintaining anticancer efficacy in ACC. Full article

(This article belongs to the Special Issue Adrenocortical Carcinoma: From Pathophysiology to Current and Emerging Therapeutic Approaches)

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17 pages, 2340 KiB

Open AccessArticle

Characterization of Direct Perturbations on Voltage-Gated Sodium Current by Esaxerenone, a Nonsteroidal Mineralocorticoid Receptor Blocker

by Wei-Ting Chang and Sheng-Nan Wu

Biomedicines 2021, 9(5), 549; https://doi.org/10.3390/biomedicines9050549 - 13 May 2021

Cited by 19 | Viewed by 2420

Abstract

Esaxerenone (ESAX; CS-3150, Minnebro^®) is known to be a newly non-steroidal mineralocorticoid receptor (MR) antagonist. However, its modulatory actions on different types of ionic currents in electrically excitable cells remain largely unanswered. The present investigations were undertaken to explore the possible [...] Read more.

Esaxerenone (ESAX; CS-3150, Minnebro^®) is known to be a newly non-steroidal mineralocorticoid receptor (MR) antagonist. However, its modulatory actions on different types of ionic currents in electrically excitable cells remain largely unanswered. The present investigations were undertaken to explore the possible perturbations of ESAX on the transient, late and persistent components of voltage-gated Na⁺ current (I_Na) identified from pituitary GH₃ or MMQ cells. GH₃-cell exposure to ESAX depressed the transient and late components of I_Na with varying potencies. The IC₅₀ value of ESAX required for its differential reduction in peak or late I_Na in GH₃ cells was estimated to be 13.2 or 3.2 μM, respectively. The steady-state activation curve of peak I_Na remained unchanged during exposure to ESAX; however, recovery of peak I_Na block was prolonged in the presence 3 μM ESAX. In continued presence of aldosterone (10 μM), further addition of 3 μM ESAX remained effective at inhibiting I_Na. ESAX (3 μM) potently reversed Tef-induced augmentation of I_Na. By using isosceles-triangular ramp pulse with varying durations, the amplitude of persistent I_Na measured at high or low threshold was enhanced by the presence of tefluthrin (Tef), in combination with the appearance of the figure-of-eight hysteretic loop; moreover, hysteretic strength of the current was attenuated by subsequent addition of ESAX. Likewise, in MMQ lactotrophs, the addition of ESAX also effectively decreased the peak amplitude of I_Na along with the increased current inactivation rate. Taken together, the present results provide a noticeable yet unidentified finding disclosing that, apart from its antagonistic effect on MR receptor, ESAX may directly and concertedly modify the amplitude, gating properties and hysteresis of I_Na in electrically excitable cells. Full article

(This article belongs to the Special Issue Adrenocortical Carcinoma: From Pathophysiology to Current and Emerging Therapeutic Approaches)

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10 pages, 4859 KiB

Open AccessArticle

Incomplete Pattern of Steroidogenic Protein Expression in Functioning Adrenocortical Carcinomas

by Sofia S. Pereira, Madalena M. Costa, Celso E. Gomez-Sanchez, Mariana P. Monteiro and Duarte Pignatelli

Biomedicines 2020, 8(8), 256; https://doi.org/10.3390/biomedicines8080256 - 30 Jul 2020

Cited by 9 | Viewed by 3200

Abstract

Autonomous steroid secretion is a common feature of adrenocortical carcinomas (ACC), although not always clinically evident owing to inefficient steroidogenesis with increased release of steroid precursors. Our study aim was to analyze the expression profile of four key proteins involved in the steroidogenesis [...] Read more.

Autonomous steroid secretion is a common feature of adrenocortical carcinomas (ACC), although not always clinically evident owing to inefficient steroidogenesis with increased release of steroid precursors. Our study aim was to analyze the expression profile of four key proteins involved in the steroidogenesis cascade, in different adrenocortical tumors. Expression of proteins involved in steroidogenesis, namely steroidogenic acute regulatory protein (StAR), 11β-hydroxylase (CYP11B1), aldosterone synthase (CYP11B2) and 17α-hydroxylase (CYP17A1), were analyzed by immunohistochemistry in ACC (n = 14), adenomas presenting with Cushing’s syndrome (ACAc) (n = 11) and clinically non-functioning adenomas (ACAn) (n = 15). A percentage of the stained area for each protein was analyzed using ImageJ software for computerized morphometric quantification. CYP11B1, StAR and CYP17A1 expression were significantly lower in ACC when compared to ACAc. In addition, ACC presented co-staining cells for CYP11B1 and CYP11B2. CYP11B1 was the steroidogenic enzyme with the most discriminative power to distinguish ACC from ACAc, with a sensitivity of 100%, specificity of 92%, and an expression higher than 4.44%, indicating the presence of a cortisol secreting adenoma. ACC depicts an incomplete pattern of steroidogenic protein expression, with decreased CYP11B1 and CYP17A1, which could explain the predominant secretion of steroid precursors. Full article

(This article belongs to the Special Issue Adrenocortical Carcinoma: From Pathophysiology to Current and Emerging Therapeutic Approaches)

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17 pages, 2866 KiB

Open AccessArticle

Astemizole Sensitizes Adrenocortical Carcinoma Cells to Doxorubicin by Inhibiting Patched Drug Efflux Activity

by Anida Hasanovic, Méliné Simsir, Frank S. Choveau, Enzo Lalli and Isabelle Mus-Veteau

Biomedicines 2020, 8(8), 251; https://doi.org/10.3390/biomedicines8080251 - 29 Jul 2020

Cited by 8 | Viewed by 2454

Abstract

Adrenocortical carcinoma (ACC) presents a high risk of relapse and metastases with outcomes not improving despite extensive research and new targeted therapies. We recently showed that the Hedgehog receptor Patched is expressed in ACC, where it strongly contributes to doxorubicin efflux and treatment [...] Read more.

Adrenocortical carcinoma (ACC) presents a high risk of relapse and metastases with outcomes not improving despite extensive research and new targeted therapies. We recently showed that the Hedgehog receptor Patched is expressed in ACC, where it strongly contributes to doxorubicin efflux and treatment resistance. Here, we report the identification of a new inhibitor of Patched drug efflux, the anti-histaminergic drug astemizole. We show that astemizole enhances the cytotoxic, proapoptotic, antiproliferative and anticlonogenic effects of doxorubicin on ACC cells at concentrations of astemizole or doxorubicin that are not effective by themselves. Our results suggest that a low concentration of astemizole sensitizes ACC cells to doxorubicin, which is a component of the standard treatment for ACC composed of etoposide, doxorubicin, cisplatin and mitotane (EDPM). Patched uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that the use of astemizole or a derivative in combination with EDPM could be a promising therapeutic option for ACC by increasing the treatment effectiveness at lower doses of EDPM, which would reduce the severe side effects of this regimen. Full article

(This article belongs to the Special Issue Adrenocortical Carcinoma: From Pathophysiology to Current and Emerging Therapeutic Approaches)

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Review

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15 pages, 1145 KiB

Open AccessReview

Surgical Management of Adrenocortical Carcinoma: Current Highlights

by Giuseppe Cavallaro, Mariarita Tarallo, Ambra Chiappini, Daniele Crocetti, Andrea Polistena, Luigi Petramala, Simone Sibio, Giorgio De Toma, Enrico Fiori and Claudio Letizia

Biomedicines 2021, 9(8), 909; https://doi.org/10.3390/biomedicines9080909 - 28 Jul 2021

Cited by 12 | Viewed by 2370

Abstract

Introduction: Adrenocortical carcinoma (ACC) is a rare tumor, often discovered at an advanced stage and associated with poor prognosis. Treatment is guided by staging according to the European Network for the Study of Adrenal Tumors (ENSAT) classification. Surgery is the treatment of choice [...] Read more.

Introduction: Adrenocortical carcinoma (ACC) is a rare tumor, often discovered at an advanced stage and associated with poor prognosis. Treatment is guided by staging according to the European Network for the Study of Adrenal Tumors (ENSAT) classification. Surgery is the treatment of choice for ACC. The aim of this review is to provide a complete overview on surgical approaches and management of adrenocortical carcinoma. Methods: This comprehensive review has been carried out according to the PRISMA statement. The literature sources were the databases PubMed, Scopus and Cochrane Library. The search thread was: ((surgery) OR (adrenalectomy)) AND (adrenocortical carcinoma). Results: Among all studies identified, 17 were selected for the review. All of them were retrospective. A total of 2498 patients were included in the studies, of whom 734 were treated by mini-invasive approaches and 1764 patients were treated by open surgery. Conclusions: Surgery is the treatment of choice for ACC. Open adrenalectomy (OA) is defined as the gold standard. In recent years laparoscopic adrenalectomy (LA) has gained more popularity. No significant differences were reported for overall recurrence rate, time to recurrence, and cancer-specific mortality between LA and OA, in particular for Stage I-II. Robotic adrenalectomy (RA) has several advantages compared to LA, but there is still a lack of specific documentation on RA use in ACC. Full article

(This article belongs to the Special Issue Adrenocortical Carcinoma: From Pathophysiology to Current and Emerging Therapeutic Approaches)

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18 pages, 1135 KiB

Open AccessReview

Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance

by Marta Araujo-Castro, Eider Pascual-Corrales, Javier Molina-Cerrillo and Teresa Alonso-Gordoa

Biomedicines 2021, 9(3), 304; https://doi.org/10.3390/biomedicines9030304 - 16 Mar 2021

Cited by 16 | Viewed by 3512

Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the [...] Read more.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy. Full article

(This article belongs to the Special Issue Adrenocortical Carcinoma: From Pathophysiology to Current and Emerging Therapeutic Approaches)

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25 pages, 2969 KiB

Open AccessReview

Adrenocortical Carcinoma: Updates of Clinical and Pathological Features after Renewed World Health Organisation Classification and Pathology Staging

by Alfred King-yin Lam

Biomedicines 2021, 9(2), 175; https://doi.org/10.3390/biomedicines9020175 - 10 Feb 2021

Cited by 26 | Viewed by 5629

Abstract

Adrenocortical carcinoma (ACC) is a heterogenous group of diseases with different clinical behaviour between adult and paediatric patients. In addition, three histological variants, oncocytic, myxoid and sarcomatoid are noted on the recent World Health Organisation (WHO) classification of ACC. A review of recent [...] Read more.

Adrenocortical carcinoma (ACC) is a heterogenous group of diseases with different clinical behaviour between adult and paediatric patients. In addition, three histological variants, oncocytic, myxoid and sarcomatoid are noted on the recent World Health Organisation (WHO) classification of ACC. A review of recent literature showed that the different types of ACC have distinctive demographic data, clinical presentation, pathology, biological behaviour, genomic and patients’ prognosis. In addition, recent updates of pathology staging for ACC allow refinement of prognostic grouping for planning treatment of the patients with ACC. These advances in genomic, pathology and staging have driven the development of standardisation of pathology reporting. International standardisation of pathological reporting of adrenocortical carcinoma and adaption to local pathology communities provide universal platforms for clinicians and researchers involved in the management of patients with ACC. To conclude, all these advances in the field of pathology will improve development of management strategies including improvement of clinical care, development of prognostic markers and testing of novel therapeutic approaches for patients with adrenocortical carcinoma. Full article

(This article belongs to the Special Issue Adrenocortical Carcinoma: From Pathophysiology to Current and Emerging Therapeutic Approaches)

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29 pages, 752 KiB

Open AccessReview

The Role of Biomarkers in Adrenocortical Carcinoma: A Review of Current Evidence and Future Perspectives

by Maja Mizdrak, Tina Tičinović Kurir and Joško Božić

Biomedicines 2021, 9(2), 174; https://doi.org/10.3390/biomedicines9020174 - 10 Feb 2021

Cited by 22 | Viewed by 4462

Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy arising from the adrenal cortex often with unexpected biological behavior. It can occur at any age, with two peaks of incidence: in the first and between fifth and seventh decades of life. Although ACC are [...] Read more.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy arising from the adrenal cortex often with unexpected biological behavior. It can occur at any age, with two peaks of incidence: in the first and between fifth and seventh decades of life. Although ACC are mostly hormonally active, precursors and metabolites, rather than end products of steroidogenesis are produced by dedifferentiated and immature malignant cells. Distinguishing the etiology of adrenal mass, between benign adenomas, which are quite frequent in general population, and malignant carcinomas with dismal prognosis is often unfeasible. Even after pathohistological analysis, diagnosis of adrenocortical carcinomas is not always straightforward and represents a great challenge for experienced and multidisciplinary expert teams. No single imaging method, hormonal work-up or immunohistochemical labelling can definitively prove the diagnosis of ACC. Over several decades’ great efforts have been made in finding novel reliable and available diagnostic and prognostic factors including steroid metabolome profiling or target gene identification. Despite these achievements, the 5-year mortality rate still accounts for approximately 75% to 90%, ACC is frequently diagnosed in advanced stages and therapeutic options are unfortunately limited. Therefore, imperative is to identify new biological markers that can predict patient prognosis and provide new therapeutic options. Full article

(This article belongs to the Special Issue Adrenocortical Carcinoma: From Pathophysiology to Current and Emerging Therapeutic Approaches)

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12 pages, 277 KiB

Open AccessReview

The Role of Immunotherapy in the Treatment of Adrenocortical Carcinoma

by Izabela Karwacka, Łukasz Obołończyk, Sonia Kaniuka-Jakubowska and Krzysztof Sworczak

Biomedicines 2021, 9(2), 98; https://doi.org/10.3390/biomedicines9020098 - 20 Jan 2021

Cited by 9 | Viewed by 3322

Abstract

Adrenocortical carcinoma (ACC) is a rare epithelial neoplasm, with a high tendency for local invasion and distant metastases, with limited treatment options. Surgical treatment is the method of choice. For decades, the mainstay of pharmacological treatment has been the adrenolytic drug mitotane, in [...] Read more.

Adrenocortical carcinoma (ACC) is a rare epithelial neoplasm, with a high tendency for local invasion and distant metastases, with limited treatment options. Surgical treatment is the method of choice. For decades, the mainstay of pharmacological treatment has been the adrenolytic drug mitotane, in combination with chemotherapy. Immunotherapy is the latest revolution in cancer therapy, however preliminary data with single immune checkpoint inhibitors showed a modest activity in ACC patients. The anti-neoplastic activity of immune checkpoint inhibitors such as anti-cytotoxic-T-lymphocyte-associated-antigen 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), and anti-PD-ligand-1 (PD-L1) antibodies in different solid tumors has aroused interest to explore the potential therapeutic effect in ACC as well. Multiple ongoing clinical trials are currently evaluating the role of immune checkpoint inhibitors in ACC (pembrolizumab, combination pembrolizumab and relacorilant, nivolumab, combination nivolumab and ipilimumab). The primary and acquired resistance to immunotherapy continue to counter treatment efficacy. Therefore, attempts are made to combine therapy: anti-PD-1 antibody and anti-CTLA-4 antibody, anti-PD-1 antibody and antagonist of the glucocorticoid receptor. The inhibitors of immune checkpoints would benefit patients with antitumor immunity activated by radiotherapy. Immunotherapy is well tolerated by patients; the most frequently observed side effects are mild. The most common adverse effects of immunotherapy are skin and gastrointestinal disorders. The most common endocrinopathy during anti-CTLA treatment is pituitary inflammation and thyroid disorders. Full article

(This article belongs to the Special Issue Adrenocortical Carcinoma: From Pathophysiology to Current and Emerging Therapeutic Approaches)

18 pages, 338 KiB

Open AccessReview

Medical Approaches in Adrenocortical Carcinoma

by Rosa Maria Paragliola, Andrea Corsello, Pietro Locantore, Giampaolo Papi, Alfredo Pontecorvi and Salvatore Maria Corsello

Biomedicines 2020, 8(12), 551; https://doi.org/10.3390/biomedicines8120551 - 29 Nov 2020

Cited by 18 | Viewed by 2706

Abstract

Adrenocortical carcinoma (ACC) represents one of the most aggressive endocrine tumors. In spite of a correct therapeutic strategy based on a multidisciplinary approach between endocrinologist, surgeon and oncologist, the prognosis is often poor. Surgery is the mainstay treatment in ACC. Mitotane, a dichloro-diphenyl-trichloro-ethane [...] Read more.

Adrenocortical carcinoma (ACC) represents one of the most aggressive endocrine tumors. In spite of a correct therapeutic strategy based on a multidisciplinary approach between endocrinologist, surgeon and oncologist, the prognosis is often poor. Surgery is the mainstay treatment in ACC. Mitotane, a dichloro-diphenyl-trichloro-ethane derivate, represents the main medical treatment of ACC in consideration of its adrenocytolitic activity and it is mainly employed as adjuvant treatment after complete surgical resection and for the treatment of advanced ACC. However, the use of mitotane as adjuvant therapy is still controversial, also in consideration of the retrospective nature of several studies. The recurrence of disease is frequent, especially in advanced disease at the diagnosis. Therefore, in these contexts, conventional chemotherapy must be considered in association with mitotane, being the combination etoposide, doxorubicin and cisplatin (EDP) the standard of care in this setting. A more modern therapeutic approach, based on the need of a salvage therapy for advanced ACC that progresses through first-line EDP, is focused on molecular-targeted therapies. However, robust clinical trials are necessary to assess the real efficacy of these treatments. Full article

(This article belongs to the Special Issue Adrenocortical Carcinoma: From Pathophysiology to Current and Emerging Therapeutic Approaches)

23 pages, 496 KiB

Open AccessReview

The Role of Satellite Glial Cells, Astrocytes, and Microglia in Oxaliplatin-Induced Neuropathic Pain

by Ji Hwan Lee and Woojin Kim

Biomedicines 2020, 8(9), 324; https://doi.org/10.3390/biomedicines8090324 - 2 Sep 2020

Cited by 37 | Viewed by 5028

Abstract

Oxaliplatin is a third-generation platinum-based chemotherapeutic drug. Although its efficacy against colorectal cancer is well known, peripheral neuropathy that develops during and after infusion of the agents could decrease the quality of life of the patients. Various pathways have been reported to be [...] Read more.

Oxaliplatin is a third-generation platinum-based chemotherapeutic drug. Although its efficacy against colorectal cancer is well known, peripheral neuropathy that develops during and after infusion of the agents could decrease the quality of life of the patients. Various pathways have been reported to be the cause of the oxaliplatin-induced paresthesia and dysesthesia; however, its mechanism of action has not been fully understood yet. In recent years, researchers have investigated the function of glia in pain, and demonstrated that glia in the peripheral and central nervous system could play a critical role in the development and maintenance of neuropathic pain. These results suggest that targeting the glia may be an effective therapeutic option. In the past ten years, 20 more papers focused on the role of glia in oxaliplatin-induced thermal and mechanical hypersensitivity. However, to date no review has been written to summarize and discuss their results. Thus, in this study, by reviewing 23 studies that conducted in vivo experiments in rodents, the change of satellite glial cells, astrocytes, and microglia activation in the dorsal root ganglia, spinal cord, and the brain of oxaliplatin-induced neuropathic pain animals is discussed. Full article

(This article belongs to the Special Issue Adrenocortical Carcinoma: From Pathophysiology to Current and Emerging Therapeutic Approaches)

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17 pages, 4198 KiB

Open AccessReview

The Potential of Steroid Profiling by Mass Spectrometry in the Management of Adrenocortical Carcinoma

by Claudia Rossi, Ilaria Cicalini, Sara Verrocchio, Giulia Di Dalmazi, Luca Federici and Ines Bucci

Biomedicines 2020, 8(9), 314; https://doi.org/10.3390/biomedicines8090314 - 28 Aug 2020

Cited by 9 | Viewed by 4249

Abstract

Radiological and endocrinological work up of adrenal neoplasms is aimed at distinguishing between frequent non-functioning adenomas and rare but very aggressive adrenocortical carcinoma (ACC). Relevant research has addressed the identification of molecular, genetic and hormonal markers that could have clinical significance for malignancy, [...] Read more.

Radiological and endocrinological work up of adrenal neoplasms is aimed at distinguishing between frequent non-functioning adenomas and rare but very aggressive adrenocortical carcinoma (ACC). Relevant research has addressed the identification of molecular, genetic and hormonal markers that could have clinical significance for malignancy, as well as a prognostic value. Regarding endocrine aspects, attention has been paid to the pattern of steroid secretion that can be affected by altered steroidogenic pathway in ACC. The advent of mass spectrometry techniques has overcome many limitations usually associated with immunoassays, allowing the determination of both common and rarely measured steroids in a single analysis with high specificity and sensitivity. Indeed, mass spectrometry strategies may be able to identify an individualized steroid profile of ACC, allowing a rapid diagnosis and a specific follow-up. In this review, insights, strengths and limitations of mass spectrometry-based approaches in steroid profiling, as well as of immunoassay in steroid measurements, will be specifically discussed. Moreover, the latest findings on steroid profiling by mass spectrometry-based techniques, the most promising analytical tool, will be summarized to evaluate if steroid profiling might be the clue for solving the clinical dilemma in differentiating ACC from non-functioning adrenocortical adenomas (ACA). Full article

(This article belongs to the Special Issue Adrenocortical Carcinoma: From Pathophysiology to Current and Emerging Therapeutic Approaches)

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