European Network For The Study Of Adrenal Tumors Research Articles

Clinical and Pathological Predictors of Death for Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare and lethal disease with a poor prognosis. This study aims to share our 41-year experience as a referral center, focusing on identifying risk factors associated with ACC mortality. Our retrospective analysis included a cohort of 150 adult patients with ACC in all stage categories, treated between 1981 and 2022. Tumor hormonal hypersecretion was observed in 78.6% of the patients, and the median age of diagnosis was 40 years. The majority presented as European Network for the Study of Adrenal Tumors (ENSAT) III or IV (22.9% and 31.2%, respectively), and the overall mortality rate was 54.6%. Independent predictors of death were elevated secretion of cortisol (HR = 2.0), androstenedione (HR = 2.2), estradiol (HR = 2.8), 17-OH progesterone (HR = 2.0), and 11-deoxycortisol (HR = 5.1), higher Weiss (HR = 4.3), modified Weiss (HR = 4.4), and Helsinki scores (HR = 12.0), advanced ENSAT stage (HR = 27.1), larger tumor size (HR = 2.7), higher Ki-67 percentage (HR = 2.3), and incomplete surgical resection (HR = 2.5). Mitosis greater than 5/50 high-power field (HR = 5.6), atypical mitosis (HR = 2.3), confluent necrosis (HR = 15.4), venous invasion (HR = 2.8), and capsular invasion (HR = 2.4) were also identified as independent predictors of death. Knowing the risk factors for ACC's mortality may help determine the best treatment option.

THU617 Prolonged Exposure To Target Mitotane Concentrations Is Associated With Better Recurrence-free Survival In Patients With Adrenocortical Carcinoma On Adjuvant Treatment

Abstract Disclosure: S. Puglisi: None. A. Calabrese: None. V. Basile: None. O. Kimpel: Speaker; Self; HRA Pharmaceuticals. B. Altieri: None. A. Angelousi: None. G. Kaltsas: None. U. Ambroziak: None. M.L. Appetecchia: None. M. Arosio: None. A. Berruti: Advisory Board Member; Self; HRA Pharmaceuticals. D. Cosentini: None. L. Canu: None. F. Ceccato: None. G. Di Dalmazi: None. L. Bouys: None. R. Libè: None. K. Nowak: None. L. Papierska: None. J. Pittaway: None. T. Kienitz: None. M. Quinkler: None. Y. Elhassan: None. C. Ronchi: None. L. Saiegh: None. A. Stigliano: None. T. Dusek: None. D. Kastelan: None. M. Fassnacht: None. M. Terzolo: Advisory Board Member; Self; HRA Pharmaceuticals. Grant Recipient; Self; HRA Pharmaceuticals. Background: The management of adjuvant mitotane therapy in patients with adrenocortical carcinoma (ACC) is challenging. Plasma mitotane concentrations >14 mg/L have been associated with efficacy in the treatment of advanced ACC; however, data in the adjuvant setting are mixed. Moreover, there is no consensus on how to assess the optimal exposure to mitotane and all the proposed methods have inherent limitations. We have recently proposed a new method analogous to what is established for the anticoagulant warfarin, the time in target range (TTR). We aimed to evaluate whether the TTR is a factor influencing recurrence-free survival (RFS) in patients with ACC on adjuvant mitotane. Methods: This is an international, retrospective, cohort study undertaken in 18 centers in 8 countries, under the auspices of the European Network for the Study of Adrenal Tumors (ENSAT), including adult patients with ACC treated with adjuvant mitotane for at least 1 year following tumor resection, with the availability of at least 3 mitotane measurements per year. TTR was calculated with the Rosendaal method and expressed as the number of months with plasma mitotane concentration >14 mg/L. The following potential predictive factors for RFS have been investigated: patient sex and age, ENSAT stage, hormone secretion, resection status, Weiss score, Ki67 index, and TTR. Data are expressed as median and interquartile range. Results: From a total of 254 patients, 157 fulfilled inclusion criteria and were analyzed (F/M 94/63; age 49, 41-58 years), with a follow-up of 49 (33-92) months. The key baseline features were: 7.0% stage I, 69.4% II, 22.3% III, 1.3% IV; 51.6% secreting tumors; 87.2% R0, 2.6% R1, 10.2% RX; Weiss score 5 (4-7); Ki67 index 11 (5-20). All patients were treated with mitotane for 25 (22-36) months, with a TTR of 14 (6-21) months. At multivariate analysis, Ki67 index (HR 1.07, 95%CI, 1.02-1.12; p<0.01) and Weiss score (HR 1.7, 95%CI, 1.16-2.47; p<0.01) were associated with an increased risk of recurrence, while female sex (HR 0.14, 95%CI, 0.04-0.58; p<0.01) and TTR (HR 0.80, 95%CI, 0.70-0.90; p<0.001) were associated with a reduced risk. Conclusions The present findings show that the patients who are exposed to plasma mitotane >14 mg/L for longer periods have better RFS. These findings provide indirect evidence of the value of adjuvant therapy with mitotane and support the importance of drug monitoring to guide dose adjustment in clinical practice and improve patient outcome. Presentation: Thursday, June 15, 2023

African American vs. Caucasian race/ethnicity in adrenocortical carcinoma patients.

In some primaries African American race/ethnicity predisposes to higher stage and worse survival. We tested for differences in cancer specific mortality (CSM) and other-cause mortality (OCM) in patients with adrenocortical carcinoma (ACC) according to African American vs. Caucasian race/ethnicity. We hypothesized that African Americans present with higher tumor stage and grade, do not receive the same treatment and benefit of lower survival than Caucasians. Within Surveillance, Epidemiology, and End Results database, we identified 1016 ACC patients: 123 (12.1%) African Americans vs. 893 (87.9%) Caucasians. Propensity score matching (age, sex, marital status, grade, T, N and M stages, treatment type), cumulative incidence plots Poisson-smoothing and competing risk regression (CRR) were used. Compared to Caucasians, African Americans were more frequently unmarried (56.9% vs. 35.5%, p < 0.001). No clinically meaningful or statistically significant differences were observed for age, grade, T, N, and M stages, as well as for treatment type (all p > 0.05). After propensity score matching (1:4), 123 African Americans and 492 Caucasians remained and were included in CRR analysis. In multivariable CRR models, CSM and OCM rates were not different between the two race/ethnicities (hazard ratio: 0.84, p = 0.3). In African Americans five-year CSM rates were 31.2% and 75.3% in respectively European Network for the Study of Adrenal Tumors (ENSAT) stages I-II and III-IV vs. 32.9% and 75.4% in Caucasians. Overall five-year OCM rates were 11.0% vs. 10.1% in respectively African Americans and Caucasians. Unlike other primaries, in ACC African American race/ethnicity is not associated with higher disease stage at initial diagnosis or worse survival.

Prognostic Value of Microscopic Tumor Necrosis in Adrenal Cortical Carcinoma

Adrenal cortical carcinoma (ACC) is an uncommon neoplasm with variable prognosis. Several histologic criteria have been identified as predictors of malignancy in adrenal cortical tumors. The Weiss score is the system most widely employed for diagnostic purposes, but also possesses prognostic value. We aim to determine the relative impact of each Weiss parameter on ACC patient survival. A multicenter retrospective analysis was conducted on a series of 79 conventional ACCs surgically treated at the Florence and Utrecht centers of the European Network for the Study of Adrenal Tumors (ENSAT). Weiss classification was recapitulated using principal component analysis (PCA). The Kaplan–Meier and Cox multivariate regression analyses were applied in order to estimate the prognostic power of Weiss versus other clinical parameters. PCA reduced the nine Weiss parameters to the best fitting 4-component model, each parameter clustering with a single component. Necrosis and venous invasion clustered together with the highest scores, thus establishing the most relevant component (Component 1) to explain Weiss distribution variability. Only Component 1 significantly predicted overall survival (OS, log-rank = 0.008) and disease-free survival (DFS, log-rank < 0.001). When considering the prognostic power of Weiss parameters, necrosis alone could independently assess OS (log-rank = 0.004) and DFS (log-rank < 0.001) at both the Kaplan–Meier and multivariate Cox regression analyses [hazard ratio (HR) = 7.8, 95% confidence interval [CI] = 1.0–63.5, p = 0.05, and HR = 12.2, 95% CI = 1.6–95.0, p = 0.017, respectively]. The presence of necrosis significantly shortened time to survival (TtS) and time to recurrence (TtR), 57.5 [31.5–103.5] vs 34 [12–78] months (p = 0.05) and 57.5 [31.5–103.5] vs 7 [1.0–31.5] months (p < 0.001), respectively. Our study suggests that, of the Weiss parameters, necrosis is the most powerful adverse factor and the best predictor of OS and DFS in ACC patients.

Prognostic predictors of adrenocortical carcinoma: A single-center thirty-year experience.

The prognosis of adrenocortical carcinoma (ACC) is poor but highly variable. The present study aimed to characterize patients with ACC at a single center in Taiwan and to determine the prognostic predictors of overall and progression-free survival. Medical records of patients, who were diagnosed with ACC at Taipei Veterans General Hospital between January 1992 and June 2021, were reviewed. Patient demographics, tumor characteristics, and subsequent treatment were analyzed with regard to overall survival and progression-free survival using Kaplan-Meier methods and a Cox regression model. Sixty-seven patients were included. Females (65.7%) were more susceptible to ACC, with a younger onset and active hormonal secretion. One-half of the patients exhibited distant metastases at the time of diagnosis. The European Network for the Study of Adrenal Tumours (ENSAT) stage (hazard ratio [HR] 3.60 [95% confidence interval (CI) 1.25-10.38]; p=0.018), large vessel invasion (HR 5.19 [95% CI 1.75-15.37]; p=0.003), and mitotane use (HR 0.27 [95% CI 0.11-0.70]; p=0.007) were significantly associated with overall survival (OS). There was no single factor independently associated with progression-free survival. ENSAT stage had a substantial impact on overall survival though there was no difference in OS between patients with stage II and stage III ACC. Large vessel invasion portended poor prognosis and influenced OS significantly. Moreover, mitotane only improved clinical outcomes of patients with stage IV disease.

Positive Correlation Between 18 F-FDG Uptake and Tumor-Proliferating Antigen Ki-67 Expression in Adrenocortical Carcinomas.

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. 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. 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. 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.

Adrenocortical Carcinoma: Clinical Presentation, Outcomes of Treatment and Survival Analysis from a 15-Year Experience

Background: Adrenocortical carcinoma (ACC) is a rare malignant tumor of adrenocortical origin, often with an unfavorable survival. The estimated incidence is 0.7 to 2 per million per year. Materials and Methods: The authors retrospectively reviewed all clinical data of the ACC patients that underwent surgical extirpation in the present study institution between January 2005 and December 2020. All demographic data, perioperative outcomes, survival, and predictive factors associated with mortality were analyzed. Results: Twenty-three patients were included in the present study. The median (IQR) age was 51 (38 to 61) with females predominant at 78.3%. The median (IQR) tumor size was 8.3 (5.3 to 14.8) cm. with the left side predominant at 65.2%. The most common presentation was hormone-related symptoms at 52.2% and isolated hypercortisolism at 34.8%, was the most common hormonal excess. Complete resection (R0) was achieved in 82.6% of the patients. Following the European Network for the Study of Adrenal Tumors (ENSAT) staging system, 52.2% of the patients were in stage 2. Adjuvant therapies such as radiation, mitotane, and chemotherapy, were required in 47.7% of the patients. Eight patients (34.8%) were death during the median follow up of 44 months. The estimated 1-, 2-, and 5-year overall survivals were 78.3%, 73.9%, and 65.2% respectively. The ENSAT stage 3 to 4 (HR 1.61, 95% CI 1.16 to 21.5, p=0.03), nodal metastasis (HR 2.11; 95% CI 1.36 to 50.26; p=0.02), distant metastasis (HR 1.75; 95% CI 1.16 to 28.62; p=0.03, and the neutrophil to lymphocyte ratio (NLR) of 5 or more (HR 2.66; 95% CI 1.74 to 116.81; p=0.01) were significant factors associated with disease mortality in univariate analysis. NLR of 5 or more was the only significant factor (HR 2.51, 95% CI 1.2 to 126.84; p=0.03) in multivariate analysis. Conclusion: ACC is a rare malignancy associated with aggressive behavior. Multidisciplinary approach with surgical removal is the mainstay of treatment. The high NLR of 5 or more is a significant factor associated with poor disease survival. Keywords: Adrenocortical carcinoma; Mitotane; Survival; Prognosis; Neutrophil to lymphocyte ratio

ODP021 A Feminizing Adrenocortical Carcinoma Presenting with Marie-Antoinette Syndrome

Abstract Introduction Adrenocortical carcinomas (ACCs) are rare and aggressive malignant tumors often with an unfavorable prognosis accounting for 0. 05-0.2% of all cancers. ACCs can be separated into 2 groups: Functioning (hormone-producing) and non-functioning tumors. About 60% of ACCs synthesize hormones. Hormone-secreting ACCs most commonly cause virilization or Cushing's syndrome. On very rare occasions, ACCs can lead to feminization in male subjects. Clinical manifestations are gynecomastia and/or hypogonadism. Here, we present a case of an estradiol-secreting adrenal cortical carcinoma. Case presentation A 58-year-old male presented with patchy hair loss, change in hair colour to white, loss of body hair and eyebrows, and breast tenderness. Hormone testing revealed significantly elevated estradiol came 582 pmol/L [NR&amp;lt;190] with a very low testosterone of 1.6 nmol/L [NR10-30], low FSH 0.1 mIU/mL [NR 0.95-11.5] and LH of 0.6 mIU/mL [NR1.14-8.75]. A testicular ultrasound was unremarkable. An adrenal MRI revealed an 11 cm heterogeneous right adrenal mass invading the inferior vena cava. FDG PET-CT revealed an intensely metabolically active tumor without any evidence of metastatic disease. The tumor was successfully removed via an open procedure. Histology confirmed an adrenocortical carcinoma with a Weiss score of 8 with a mitotic account of 10/50 HPF and Ki-67 labelling index of 20-25%. There was vascular invasion with large areas of necrosis, ENSAT (European Network for the Study of Adrenal Tumours) stage II. Postoperatively, he made a good clinical recovery and was offered adjuvant Mitotane and EDP (Doxorubicin, Etoposide and Cisplatin) chemotherapy. Due to a significant rise in GGT and platelets, Mitotane had to be stopped temporarily. During the course of his treatment, he developed a hoarse voice and CT neck revealed abnormal thickening of the lateral aspects of the aortic arch suggesting possible tumor recurrence or aortitis. A biopsy was not diagnostic, but did not show any features of malignancy. He completed his five cycles of EDP chemotherapy. Estradiol has remained normal and his hoarse voice improved. Conclusion We describe a rare case of an estradiol-secreting ACC presenting with feminization and Marie-Antoinette syndrome as well as possible paraneoplastic aortitis. Targeted molecular tumor analysis may guide further treatment options and enrolment in clinical trials should be considered. Presentation: No date and time listed

Comprehensive Characterization of the Regulatory Landscape of Adrenocortical Carcinoma: Novel Transcription Factors and Targets Associated with Prognosis

We reconstructed a transcriptional regulatory network for adrenocortical carcinoma (ACC) using transcriptomic and clinical data from The Cancer Genome Atlas (TCGA)-ACC cohort. We investigated the association of transcriptional regulatory units (regulons) with overall survival, molecular phenotypes, and immune signatures. We annotated the ACC regulons with cancer hallmarks and assessed single sample regulon activities in the European Network for the Study of Adrenal Tumors (ENSAT) cohort. We found 369 regulons associated with overall survival and subdivided them into four clusters: RC1 and RC2, associated with good prognosis, and RC3 and RC4, associated with worse outcomes. The RC1 and RC3 regulons were highly correlated with the 'Steroid Phenotype,' while the RC2 and RC4 regulons were highly correlated with a molecular proliferation signature. We selected two regulons, NR5A1 (steroidogenic factor 1, SF-1) and CENPA (Centromeric Protein A), that were consistently associated with overall survival for further downstream analyses. The CENPA regulon was the primary regulator of MKI-67 (a marker of proliferation KI-67), while the NR5A1 regulon is a well-described transcription factor (TF) in ACC tumorigenesis. We also found that the ZBTB4 (Zinc finger and BTB domain-containing protein 4) regulon, which is negatively associated with CENPA in our transcriptional regulatory network, is also a druggable anti-tumorigenic TF. We anticipate that the ACC regulons may be used as a reference for further investigations concerning the complex molecular interactions in ACC tumors.

Hispanic vs. Caucasian Race/Ethnicity in Adrenocortical Carcinoma Patients.

In primaries other than adrenocortical carcinoma (ACC), Hispanic race/ethnicity may predispose to higher stage at initial diagnosis and may result in worse survival. We tested the association between Hispanic race/ethnicity and cancer specific mortality (CSM) in ACC patients in addition to testing for differences in other-cause mortality (OCM) rates between Hispanics and Caucasians. Within Surveillance, Epidemiology, and End Results database (2004-2018), we identified 1,060 ACC patients: 167 (15.8%) Hispanics vs. 893 (84.2%) Caucasians. Propensity score matching (age, sex, grade, T, N and M stages, treatment types), cumulative incidence plots Poisson-smoothing and competing risk regression (CRR) were used. Compared to Caucasians, Hispanics were younger (51 vs. 57 years, p<0.001) and presented higher rates of T3-4 primary tumor stage (52.7% vs. 42.8%, p=0.007). No other statistically significant differences were observed for grade, lymph node invasion, distant metastases, European Network for the Study of Adrenal Tumors (ENSAT) stage and treatment type (p>0.05 in all cases). After matching (1:3), 167 Hispanics and 501 Caucasians remained and were included in CRR analyses. In Hispanics, five-year CSM rates were 38.0% and 78.8% in respectively ENSAT stages I-II and III-IV vs. 34.1% and 74.4% in Caucasians. Overall, five-year OCM rates were 10.7% vs. 9.0% in Hispanics and Caucasians, respectively. In multivariable CRR models, Hispanic race/ethnicity was not an independent predictor for higher CSM (hazard ratio=1.18, p=0.2). In ACC, relative to Caucasians, Hispanic race/ethnicity is associated with lower age at initial diagnosis, but not with higher tumor stage or survival disadvantage.

Adrenal insufficiency and pregnancy.

Adrenal insufficiency is a disorder characterized by the failure of adrenocortical function because of distorted function of hypothalamic-pituitary- adrenal (HPA) axis. Pregnancy is a state of a physiological glucocorticoid excess as the HPA axis is functioning at a higher level. The aim of the present review was to shed light on current evidence of adrenal insufficiency management during pregnancy, along with maternal and neonatal outcomes. A recent multicenter study under the auspices of the European Network for the Study of Adrenal Tumours (ENSAT) presented real-life data of pregnant women with adrenal insufficiency documenting an increased use of hydrocortisone (or mineralocorticoids when needed according to the level of disorder) replacement treatment, increased rates of caesarean section, preterm delivery and adrenal crises along with peripartum and postpartum complications but no maternal or neonatal fatality. These data were in agreement with those obtained from previously published studies. The limited published evidence is in line with the present guidelines as real-life data did not document any increased fatality among pregnant women or newborns. Prospective data with prolonged follow-up are needed to shed more light on appropriate dose adjustments to avoid the risks of under-replacement or over-replacement of glucocorticoid and/or mineralocorticoid drugs and their sequelae. A recent multicenter study by ENSAT presented real-life data of pregnant women with adrenal insufficiency documenting an increased use of hydrocortisone as replacement treatment during pregnancy, along with an increased rate of caesarean section and preterm delivery, adrenal crises, peripartum and postpartum complications but no maternal or neonatal fatality. These data are in agreement with those of a previously published study and also confirm the statements made by the recent guidelines. Prospective data are needed aiming to develop precise therapeutic protocols during each trimester of pregnancy according to the different causes of adrenal insufficiency.

Improved Diagnostic Accuracy of Clonidine Suppression Testing Using an Age-Related Cutoff for Plasma Normetanephrine.

Moderately elevated plasma normetanephrine (NMN) levels are frequent among patients with suspected pheochromocytoma and paraganglioma (PPGL). Clonidine suppression testing (CST) is recommended to distinguish patients with from those without PPGL. We aimed at evaluating the diagnostic outcome of CST in patients with moderate NMN elevations. Data from patients participating in the PMT study (Prospective Monoamine-Producing Tumor) and the ENSAT (European Network for the Study of Adrenal Tumours) registry in 6 European reference centers were analyzed retrospectively. Eighty-nine patients with suspected PPGL and moderate NMN elevations upon screening were included. During follow-up, PPGL was confirmed in 16 and excluded in 73 cases. Plasma NMN was measured by liquid chromatography tandem mass spectrometry before and 180 minutes after oral clonidine. Receiver operating characteristic analysis was performed to identify optimal cutoffs. If published diagnostic criteria for CST (ie, NMN ≥112 ng/L and NMN suppression <40%) were applied, a sensitivity of 88% (CI, 61%-98%) and a specificity of 97% (CI, 90%-100%) were observed. An improved cutoff for plasma NMN 180 minutes after clonidine was established at 80% of the age-related upper limit of normal, resulting in a sensitivity of 94% and a specificity of 97%. False-negative CST results occurred in 2 patients with small PPGL. This study, involving one of the largest cohorts of patients with suspected PPGL and moderately elevated NMN, confirmed the diagnostic accuracy of CST. The application of an adapted cutoff further improved sensitivity.

The Effect of Surgeon Expertise on the Outcome of Patients with Adrenocortical Carcinoma.

Complete surgical removal of adrenocortical carcinoma (ACC) represents the only chance of long-term cure. In this study, we compared the long-term outcomes of ACC patients depending on whether they had adrenal surgery performed in a high-volume (HVC) or in a low-volume (LVC) center. This retrospective study included 49 patients from the Croatian ACC Registry with the European Network for the Study of Adrenal Tumors (ENSAT) stage I–III ACC, of which 35 underwent surgery in a HVC whereas 14 of them were operated in one of the LVCs. Patients operated in the LVCs had a significantly higher rate of ACC recurrence (57.1% vs. 22.9%; p = 0.02). Accordingly, RFS was significantly longer in patients operated on in HVC (p = 0.04). The difference in RFS remained significant after controlling for age, gender, tumor size, Ki-67 index, Weiss score, and type of surgery (HR 4.55; 95% CI 1.16–17.88; p = 0.03). In addition, there is a tendency towards longer DSS in patients in the HVC group compared to those in the LVC group (p = 0.05). These results point to the centralization of adrenal surgery as a key prerequisite for improving the outcomes of ACC patients.

Multifactorial assessment of prognostic features of adrenocortical cancer

To determine the predictors of the aggressive course of adrenocortical cancer (ACC). ACC is a rare malignant neoplasm of the adrenal cortex with a variable prognosis. At present, predicting the course of the disease and clinical outcome in patients presents significant difficulties, since many aspects of the treatment of ACC have not been studied or require clarification. In particular, the prognostic value of markers that are used in clinical practice has not been fully determined. Histological and immunohistochemical studies of the surgical material of adrenal neoplasms were performed. The study included 73 patients with a histologically confirmed diagnosis of ACC: 51 (69.9%) women and 22 (30.1%) men aged 17 to 82 years. Cox regression model was used for survival analysis. Statistically significant factors (p<0.05) according to the results of independent regression analysis were included in the Kaplan-Meier analysis followed by pairwise comparison using the log-rank test. An increased risk of recurrence is associated with the presence of pathological mitoses and excessive secretion of aldosterone, death - with stage IV according to the classification of the European Network for the Study of Adrenal Tumors (ENSAT), relapse and death - the value of mitotic activity more than 20, the Ki-67 index more than 12, the classic variant. Mitotic activity and hormonal activity were independent predictors of recurrence-free survival, mitotic activity and ENSAT stage were independent predictors of overall survival. In the present work, potential predictors of the course of ACC are identified, which are available for use in routine practice. Based on the totality of clinical, morphological, immunohistochemical data used in the diagnosis of ACC, a conception of the patient's survival can be obtained.

Surgical Management of Adrenocortical Carcinoma: Current Highlights.

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.

ENSAT registry-based randomized clinical trials for adrenocortical carcinoma.

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.

Adrenocortical Carcinoma in Eight Children: A Report and Literature Review.

ObjectiveThis study aimed to summarize the clinical characteristics, comprehensive treatment, and prognosis of adrenocortical carcinoma (ACC) in children.MethodsThe clinical data of eight children with definite diagnoses of ACC were retrospectively analyzed, and statistical methods were used to analyze the clinical characteristics, comprehensive treatment mode, and prognosis of these patients.Results(1) Clinical characteristics: two were males and six were females with the median age of onset was six-years old were involved. Four patients had a rash and precocious puberty as the symptoms of onset. European Network for the Study of Adrenal Tumors (ENSAT) staging: stage II, two patients; stage IV, six patients. (2) Comprehensive treatment: all eight patients underwent surgical treatment and received six cycles of chemotherapy: the regimen was “etoposide + pirarubicin + cisplatin + mitotane.” (3) Prognosis analysis: among these eight patients, two patients died, two patients achieved complete remission, the disease was stable in four patients, and the overall five-year survival rate was 75%. Prognosis analyzed according to ENSAT staging (stage II versus stage IV) revealed that two-year survival rates of the two groups were 100% versus 65%, respectively, without statistical significant (χ2 = 1.066, P = 0.302). Prognosis analyzed according to Weiss score (Weiss score was <6, five patients;≥6, three patients) revealed That survival time of the two groups was 50±9.52 months versus 6±1.70 months, the two-year survival rates of the two groups were 100% versus 35%, and the difference in survival rates between these two groups was statistically significant (χ2 = 4.091, P = 0.043).ConclusionThe Weiss score is an important prognostic factor for ACC. The chemotherapy regimen “mitotane + etoposide + adriamycin + cisplatin” is recommended.

RNA Sequencing and Somatic Mutation Status of Adrenocortical Tumors: Novel Pathogenetic Insights.

Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure. To investigate the relationship between transcriptome profile and genetic background in a large series of adrenocortical tumors and identify new potential pathogenetic mechanisms. Cross-sectional study. University Hospitals of the European Network for the Study of Adrenal Tumors (ENSAT). We collected snap-frozen tissue from patients with adrenocortical tumors (n = 59) with known genetic background: 26 adenomas with Cushing syndrome (CS- cortisol-producing adenoma [CPA]), 17 adenomas with mild autonomous cortisol secretion (MACS-CPAs), 9 endocrine-inactive adenomas (EIAs), and 7 adrenocortical carcinomas (ACCs). Ribonucleic acid (RNA) sequencing. Gene expression, long noncoding RNA (lncRNA) expression, and gene fusions. Correlation with genetic background defined by targeted Sanger sequencing, targeted panel- or whole-exome sequencing. Transcriptome analysis identified 2 major clusters for adenomas: Cluster 1 (n = 32) mainly consisting of MACS-CPAs with CTNNB1 or without identified driver mutations (46.9% of cases) and 8/9 EIAs; Cluster 2 (n = 18) that comprised CP-CPAs with or without identified driver mutation in 83.3% of cases (including all CS-CPAs with PRKACA mutation). Two CS-CPAs, 1 with CTNNB1 and 1 with GNAS mutation, clustered separately and relatively close to ACC. lncRNA analysis well differentiate adenomas from ACCs. Novel gene fusions were found, including AKAP13-PDE8A in one CS-CPA sample with no driver mutation. MACS-CPAs and EIAs showed a similar transcriptome profile, independently of the genetic background, whereas most CS-CPAs clustered together. Still unrevealed molecular alterations in the cAMP/PKA or Wnt/beta catenin pathways might be involved in the pathogenesis of adrenocortical tumors.

Management of adrenocortical carcinoma in Western Australia: a perspective over 14 years.

Adrenocortical carcinoma is a rare but aggressive form of endocrine neoplasm that confers a poor prognosis. To date, the only Australian data published is from New South Wales. This paper describes our experience in Western Australia with a focus on surgical approach and outcomes. A retrospective study of patients treated for adrenocortical carcinoma in Western Australia over 14 years was performed. Over the 14-year period, a total of 33 patients underwent surgery for adrenocortical carcinoma. Resection outcomes were superior in an open en bloc approach with an 85% R0 margin (P = 0.007). Local recurrence rates were lowest in an open en bloc approach (11%) compared to laparoscopic (75%). Multivariate analysis showed that an en bloc resection is highly correlated with an R0 resection (P < 0.05) and significantly associated with lower (odds ratio = 0.06) local recurrence (P = 0.009). Higher volume surgeons (>5 cases) had lower operative times and blood loss. Compliance with mitotane was significantly improved with close monitoring of levels. The European Network for the Study of Adrenal Tumours (ENSAT) stage at presentation was most predictive of long-term survival with 100% of stage I patients alive compared to 53% of stage II, 25% of stage III and 17% of stage IV patients at the end of the follow-up period. An open en bloc approach with a low threshold for multi-visceral resection performed by high volume surgeons have improved outcomes in local recurrence, operative times and blood loss.

Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma.

BackgroundAdrenocortical carcinoma (ACC) is a rare endocrine malignancy. Tumor-related glucocorticoid excess is present in ~60% of patients and associated with particularly poor prognosis. Results of first clinical trials using immune checkpoint inhibitors were heterogeneous. Here we characterize tumor-infiltrating T lymphocytes (TILs) in ACC in association with glucocorticoids as potential explanation for resistance to immunotherapy.MethodsWe performed immunofluorescence analysis to visualize tumor-infiltrating T cells (CD3+), T helper cells (CD3+CD4+), cytotoxic T cells (CD3+CD8+) and regulatory T cells (Tregs; CD3+CD4+FoxP3+) in 146 ACC tissue specimens (107 primary tumors, 16 local recurrences, 23 metastases). Quantitative data of immune cell infiltration were correlated with clinical data (including glucocorticoid excess).Results86.3% of ACC specimens showed tumor infiltrating T cells (7.7 cells/high power field (HPF)), including T helper (74.0%, 6.7 cells/HPF), cytotoxic T cells (84.3%, 5.7 cells/HPF) and Tregs (49.3%, 0.8 cells/HPF). The number of TILs was associated with better overall survival (HR for death: 0.47, 95% CI 0.25 to 0.87), which was true for CD4+− and CD8+ subpopulations as well. In localized, non-metastatic ACC, the favorable impact of TILs on overall and recurrence-free survival was manifested even independently of ENSAT (European Network for the Study of Adrenal Tumors) stage, resection status and Ki67 index. T helper cells were negatively correlated with glucocorticoid excess (Phi=−0.290, p=0.009). Patients with glucocorticoid excess and low TILs had a particularly poor overall survival (27 vs. 121 months in patients with TILs without glucocorticoid excess).ConclusionGlucocorticoid excess is associated with T cell depletion and unfavorable prognosis. To reactivate the immune system in ACC by checkpoint inhibitors, an inhibition of adrenal steroidogenesis might be pivotal and should be tested in prospective studies.