Adult Adrenocortical Carcinoma Research Articles

Estimation of the tumor size at cure threshold among adult patients with adrenocortical carcinoma: A populational-based study

BackgroundThe prognostic significance of tumor size with adrenocortical carcinoma (ACC) patients has not yet been thoroughly evaluated. Our objective was to investigate the influence of tumor size on prognostic value in adult ACC patients. MethodsThe Surveillance, Epidemiology and End Results Program (SEER) was employed to identify adult ACC patients who had been diagnosed from 2004 to 2015. The “X-Tile” program determined the optimal cutoff value of tumor size. Cancer-specific survival (CSS) and overall survive (OS) were estimated. The survival outcomes and risk factors were analyzed by the Kaplan-Meier methods and the multivariable cox regression respectively. ResultsA total 426 adult ACC patients were included. Univariable and multivariable cox analysis revealed age, larger tumor size and metastasis as consistent predictors of lower CSS and OS. The optimal cutoff value of tumor size was identified as 8.5 cm using X-tile software, and Kaplan-Meier method showed dramatic prognostic difference between patients with larger tumors (＞8.5 cm) and smaller tumors (≤8.5 cm) (log-rank test, P < 0.001). Subgroup analyses revealed no statistical significance and a consistent proportionate effect of tumor size on CSS and OS across all eight pre-specified subgroups. Interestingly, an additional subgroup analysis showed that ACC patients could not benefit from chemotherapy in terms of CSS and OS. ConclusionThe study suggests that tumor size is a crucial prognostic factor in ACC patients and a cutoff value 8.5 cm might indicate a poor outcome. Given the limitations of the available data, it is challenging to conclusively determine the benefit of chemotherapy in adult ACC patients across different tumor size ranges.

Lamin B1: a novel biomarker in adult and pediatric adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a malignancy with a poor prognosis and high mortality rate. A high tumor mutational burden (TMB) has been found to be associated with poor prognosis in ACC. Thus, exploring ACC biomarkers based on TMB holds significant importance for patient risk stratification. In our research, we utilized weighted gene coexpression network analysis and an assay for transposase-accessible chromatin with high-throughput sequencing to identify genes associated with TMB. Through the comprehensive analysis of various public datasets, Lamin B1 (LMNB1) was identified as a biomarker associated with a high TMB and low chromatin accessibility. Immunohistochemical staining demonstrated high expression of LMNB1 in ACC compared to noncancerous tissues. Functional enrichment analyses revealed that the function of LMNB1 is associated with cell proliferation and division. Furthermore, cell assays suggested that LMNB1 promotes tumor proliferation and invasion. In addition, mutation analysis suggested that the high expression of LMNB1 is associated with TP53 mutations. Additionally, LMNB1 was highly expressed in the vast majority of solid tumors across cancers. In our immune analysis, we discovered that the high expression of LMNB1 might suppress the infiltration of CD8+ T cells in the ACC microenvironment. In summary, LMNB1 is a predictive factor for the poor prognosis of adult and pediatric ACC. Its high expression in ACC is positively associated with high TMB and lower chromatin accessibility, and it promotes ACC cell proliferation and invasion. Therefore, LMNB1 holds promise as a novel biomarker and potential therapeutic target for ACC.

Adrenocortical carcinoma: A tumor with poor answer to classic chemotherapy

Abstract Introduction: Adrenocortical carcinoma (ACC) represents a rare endocrine malignancy being the second most aggressive endocrine cancer after anaplastic thyroid cancer. [1]. While most of them arise sporadically, up to 15% of adult ACC patients are related to germline mutations associated with familial cancer syndromes.[1,2]. Current treatment strategies include surgery as well as systemic therapy with mitotane and chemotherapy. Case report: A 60-year-old female patient with a family history of colon cancer, multinodular goiter, hypothyroidism treated with substitutive therapy, uterine fibroids, and hypertension, was diagnosed with adrenocortical carcinoma. No distant metastasis were present at the moment of diagnosis so an adrenalectomy was performed. Due to postoperative complications, a total nephrectomy was also needed. Adjuvant Mitotane treatment was given. A CT exam performed 5 months after the resection showed multiple pulmonary metastasis, a liver nodule and peritoneal carcinomatosis. The standard first-line chemotherapy of choice was Carboplatin and Etoposide. After completing 3 cycles of chemotherapy the imaging reassessment show the progression of liver and peritoneal lesions and the quasi-complete regression of lung lesions. Currently, the Mitotate treatment was stopped due to severe adverse reactions. Conclusions: Adrenocortical carcinoma is a rare endocrine malignancy with a poor prognosis. The recruitment of ACC patients for new clinical trials to investigate new treatment strategies is needed because currently, no significant therapeutic breakthrough is emerging.

Advances in translational research of the rare cancer type adrenocortical carcinoma.

Adrenocortical carcinoma is a rare malignancy with an annual worldwide incidence of 1-2 cases per 1 million and a 5-year survival rate of <60%. Although adrenocortical carcinoma is rare, such rare cancers account for approximately onethird of patients diagnosed with cancer annually. In the past decade, there have been considerable advances in understanding the molecular basis of adrenocortical carcinoma. The genetic events associated with adrenocortical carcinoma in adults are distinct from those of paediatric cases, which are often associated with germline or somatic TP53 mutations and have a better prognosis. In adult primary adrenocortical carcinoma, the main somatic genetic alterations occur in genes that encode proteins involved in the WNT-β-catenin pathway, cell cycle and p53 apoptosis pathway, chromatin remodelling and telomere maintenance pathway, cAMP-protein kinase A (PKA) pathway or DNA transcription and RNA translation pathways. Recently, integrated molecular studies of adrenocortical carcinomas, which have characterized somatic mutationsand the methylome as well as gene and microRNA expression profiles, have led to a molecular classification of these tumours that can predict prognosis and have helped to identify new therapeutic targets. In this Review, we summarize these recent translational research advances in adrenocortical carcinoma, which it is hoped could lead to improved patient diagnosis, treatment and outcome.

Prognostic Factors of Adrenocortical Carcinoma: Experience from a Regional Medical Center in Eastern China.

This study aimed to summarize and analyze the clinical and pathological features and prognostic risk factors of adrenocortical carcinoma (ACC). We retrospectively analyzed clinical and pathological data and the prognoses of 39 adult ACC patients confirmed by pathologic diagnosis at the Affiliated Hospital of Qingdao University between August 2009 and October 2021. Kaplan-Meier curves and univariate and multivariate Cox regression models were used to analyze correlations between clinical and pathological parameters and prognosis. A nomogram prediction model was constructed for overall survival (OS) based on the independent prognostic factors and externally validated it with The Cancer Genome Atlas (TCGA) dataset. The mean age of the patient cohort was 53.87 ± 11.1 years (range: 29-80 years), which included 17 men and 22 women. The 1-, 2-, and 5-year OS rates were 83.7%, 64.4%, and 59.8%, respectively; the recurrence-free survival (RFS) rates at the same time points were 76.1%, 45.8%, and 23.5%, respectively. Kaplan-Meier curves showed that patients with poor OS were associated with M1 stage (P = 0.008), late ENSAT stage (P = 0.017), presence of venous tumor thrombus (P = 0.015), Ki67 >20% (P = 0.006), R1/R2 status (P = 0.018), and poorly differentiated tumors (P = 0.047). Patients with late ENSAT stage (P = 0.017), combined with venous tumor thrombus (P = 0.008), Ki67 >20% (P = 0.022) were more likely to have tumor recurrence. However, age, gender, BMI, tumor diameter, clinical symptoms and postoperative treatment were not correlated with OS or RFS (P > 0.05). Univariate and multivariate COX analyses showed that Ki67 >20% (P = 0.013) and R1/2 status (P = 0.040) were independent risk factors for OS, while only Ki67 >20% (P = 0.032) was an independent risk factor for RFS. A nomogram for predicting OS was constructed based on the above factors, and the area under the receiver characteristic curve (ROC)-1, 3, and 5-year survival were 0.8, 0.825 and 0.902, respectively. The C-index of the predicted nomogram was 0.813 and a high C-index value of 0.846 could still be achieved in the external validation of TCGA. ACC is a rare and deadly endocrine malignancy with a high rate of recurrence. High Ki67 index (>20%) and R1/R2 resection status were independent risk factors for poor prognosis in ACC patients. A novel nomogram with a relatively good accuracy was established to assist clinicians in assessing the risk of OS in patients with ACC.

Pediatric adrenocortical carcinoma.

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 TP53 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.

FINDING THE CULPRIT: A RARE CASE OF METASTATIC ADRENOCORTICAL CARCINOMA TO THE LUNG WITH CONCURRENT PRIMARY NEUROENDOCRINE TUMOR OF THE LUNG

TOPIC: Lung Cancer TYPE: Medical Student/Resident Case Reports INTRODUCTION: Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 1 - 2 million cases per year. Most ACCs are sporadic and nonfunctioning which leads to incidental discovery. However, they are frequently aggressive tumors that are systemically advanced at the time of diagnosis. CASE PRESENTATION: A 66-year-old male smoker with coronary artery disease, hypertension, and mitral regurgitation was admitted for one month of progressively worsening dyspnea and bilateral lower extremity edema. Initial labs revealed BNP of 1,136 pg/ml with normal EKG. However, chest x-ray showed countless nodules throughout the bilateral lungs. CT revealed a 15 cm adrenal mass and innumerable pulmonary nodules suggesting metastatic disease. After 24-hour urine metanephrine resulted in normal range, a core biopsy of the adrenal gland showed focal areas of clear cells with abnormal mitoses and necrosis while staining positive for Melan A, inhibin, and calretinin. These findings were consistent with ACC. After outside records were obtained, patient was noted to have recent lung biopsy that was morphologically and immunohistochemically unique, instead showing uniform cells with synaptophysin and chromogranin positivity. A 68-Gallium Dotatate PET/CT then confirmed an intensely tracer-avid 2.5 cm right middle lobe tumor most consistent with a primary neuroendocrine tumor (NET) of the lung. On the other hand, the remaining lung nodules and adrenal mass demonstrated low-level uptake and consequently were determined to be from primary ACC. The patient was started on etoposide, doxorubicin, and cisplatin with mitotane (EDP-M) for metastatic ACC treatment. DISCUSSION: This case demonstrates a unique case of two primary cancers with extensive pulmonary metastases secondary to ACC. NETs produce increased neurosecretory granules reflected in expression of markers such as chromogranin A and synaptophysin, while ACC expresses Melan A, inhibin, and calretinin. Malignant ACC can further be classified using the Weiss criteria: >6 mitoses per 50 high-power fields, <25% clear tumor cells, abnormal mitoses, necrosis, and capsular invasion. In addition, 68-Gallium Dotatate PET/CT can detect the somatostatin receptors found in NETs. The standard of care is recommended based on the FIRM-ACT trial that showed superiority of the 4-drug regimen EDP-M. CONCLUSIONS: In this unusual case of primary NET of the lung and primary ACC, the 68-Gallidium Dotatate PET/CT can determine the type of tumor that metastasized to the lung. Metastatic ACC is very challenging to treat and currently, EDP-M offers the best chance of extending survival. REFERENCE #1: Fassnacht, M. et al. 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. Eur J Endocrinol 179, G1–G46 (2018). REFERENCE #2: Else, T. et al. Adrenocortical carcinoma. Endocr Rev 35, 282–326 (2014). REFERENCE #3: Kerkhofs, T. M. A. et al. Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993. Eur J Cancer 49, 2579–2586 (2013). DISCLOSURES: No relevant relationships by Minira Aslanova, source=Web Response No relevant relationships by Karishma Rupani, source=Web Response No relevant relationships by Sawan Rupani, source=Web Response No relevant relationships by Lesley Wu, source=Web Response

Different management of adrenocortical carcinoma in children compared to adults: is it time to share guidelines?

Pediatric and adult adrenocortical carcinomas differ in many respects but treatment is often similar in both age groups. The Journal of Clinical Oncology recently published the results of a risk-stratified single-arm interventional trial conducted by the Children’s Oncology Group in which 77 patients were treated in three different interventional cohorts. In this Point of View paper we comment on the treatment strategies adopted within the ARAR0332 trial in terms of surgery approach, duration of adjuvant therapies, and palliative chemotherapy. We focus on the differences in the treatment of pediatric ACC patients compared to the ESE/ENSAT and ESMO guidelines released in 2018 for adult patients. For example, patients in stratum 3 and 4 received 8 (instead of 6) cycles of EDP chemotherapy but 8 months (instead of 24) of mitotane adjuvant therapy. Bearing clearly in the mind that pediatric and adult ACC patients represent different settings, we wonder whether there could be some areas of intervention overlapping to constitute a continuum of disease across ages. Thus, pediatric and adult cohoperative groups should be encouraged to collaborate in order to reach common guidelines for the treatment of such a rare disease.

Childhood Adrenocortical Carcinoma: A Case Report

Adrenal tumors can arise either from cortex or from medulla; both the regions being structurally and functionally different. They are categorized as functional (hormone-secreting) or silent and as either benign or malignant. Adrenocortical Carcinoma (ACC) are rare tumors that have a bimodal distribution, although most adult ACC are non-functional, in pediatric age group, nearly 95% are functional Our case report is presented because of its rarity consisting of our patient with virilising signs at the age of one and a half years.

Low Protein Expression of ATRX and ZNRF3 as a Novel Prognostic Marker of Adult Adrenocortical Carcinoma

Abstract Adrenocortical carcinoma (ACC) is a rare malignant neoplasia that is usually associated with a dismal prognosis. ACC overall survival (OS) depends on the particular biology of the tumor. Pan-genomic studies have demonstrated the involvement of ATRX and ZNRF3 genes in adrenocortical tumorigenesis. Aim: To evaluate ATRX and ZNRF3 protein expression in a large cohort of adults with ACC followed at a single tertiary referral center to establish the prognostic value of these genes. Methods: Two pathologists analyzed immunohistochemically-stained slides for ATRX and ZNRF3 (blinded assessment) proteins using tissue microarrays comprising tissue samples from 82 ACC (kappa 0.854; P&amp;lt;0.001). Cohort: female 76.8%; median age 38.2 (15.3–85.4) years; 67.5% of patients presented with hypercortisolism; ENSAT stage 1, 11.12%; 2, 44.44%; 3 and 4: (44.44%). The median follow-up time was 39.58 (1.4–406.8) months; 39 patients died during this period. Low protein expression was defined as follows: ATRX, when &amp;lt; 25% of tumor cells were immunoreacted; ZNRF3, when a score &amp;lt; 3 (extension + intensity) was established. Results: Low ATRX protein expression was positively associated with the age at diagnosis (P&amp;lt; 0.001), and it was negatively correlated with tumor size (P=0.020) and with Weiss score (P=0.033). Low ZNRF3 protein expression correlated negatively with tumor weight (P=0.026), with tumor size (P= 0.005), and with Weiss score (P=0.002). Regarding OS, the low protein expression of ATRX and ZNRF3 was associated with a decrease of OS (P=0.045 and P=0.012, respectively). The Cox model for ATRX protein expression showed a HR of 0.521 (95% CI 0.273–0.997; P=0.049); for ZNRF3 expression, HR = 0.441 (95% CI 0.229–0.852; P=0.015). The combined protein expression of both genes was also associated with a decrease in OS in this cohort (P=0.02). The high ATRX and ZNRF3 protein expressions were positively associated with optimistic recurrence-free survival (P=0.027, P=0.005, respectively). Conclusion: The knowledge of tumor biology is an important step to deliver personalized medicine, affording the opportunity to design better clinical approaches and targeted therapies. This study brought pan-genomic studies closer to clinical practice with an easily accessible tool for stratifying patients with ACC. We demonstrated that low levels of protein expression of ATRX and ZNRF3 are negative prognostic markers of ACC.

Construction of a robust prognostic model for adult adrenocortical carcinoma: Results from bioinformatics and real-world data.

This study aims to construct a robust prognostic model for adult adrenocortical carcinoma (ACC) by large‐scale multiomics analysis and real‐world data. The RPPA data, gene expression profiles and clinical information of adult ACC patients were obtained from The Cancer Proteome Atlas (TCPA), Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Integrated prognosis‐related proteins (IPRPs) model was constructed. Immunohistochemistry was used to validate the prognostic value of the IPRPs model in Fudan University Shanghai Cancer Center (FUSCC) cohort. 76 ACC cases from TCGA and 22 ACC cases from GSE10927 in NCBI’s GEO database with full data for clinical information and gene expression were utilized to validate the effectiveness of the IPRPs model. Higher FASN (P = .039), FIBRONECTIN (P < .001), TFRC (P < .001), TSC1 (P < .001) expression indicated significantly worse overall survival for adult ACC patients. Risk assessment suggested significantly a strong predictive capacity of IPRPs model for poor overall survival (P < .05). IPRPs model showed a little stronger ability for predicting prognosis than Ki‐67 protein in FUSCC cohort (P = .003, HR = 3.947; P = .005, HR = 3.787). In external validation of IPRPs model using gene expression data, IPRPs model showed strong ability for predicting prognosis in TCGA cohort (P = .005, HR = 3.061) and it exhibited best ability for predicting prognosis in GSE10927 cohort (P = .0898, HR = 2.318). This research constructed IPRPs model for predicting adult ACC patients’ prognosis using proteomic data, gene expression data and real‐world data and this prognostic model showed stronger predictive value than other biomarkers (Ki‐67, Beta‐catenin, etc) in multi‐cohorts.

Low Protein Expression of both ATRX and ZNRF3 as Novel Negative Prognostic Markers of Adult Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignancy that is associated with a dismal prognosis. Pan-genomic studies have demonstrated the involvement of ATRX and ZNRF3 genes in adrenocortical tumorigenesis. Our aims were to evaluate the protein expression of ATRX and ZNRF3 in a cohort of 82 adults with ACC and to establish their prognostic value. Two pathologists analyzed immuno-stained slides of a tissue microarray. The low protein expression of ATRX and ZNRF3 was associated with a decrease in overall survival (OS) (p = 0.045, p = 0.012, respectively). The Cox regression for ATRX protein expression of >1.5 showed a hazard ratio (HR) for OS of 0.521 (95% CI 0.273–0.997; p = 0.049) when compared with ≤1.5; for ZNRF3 expression >2, the HR for OS was 0.441 (95% CI, 0.229–0.852; p = 0.015) when compared with ≤2. High ATRX and ZNRF3 protein expressions were associated with optimistic recurrence-free survival (RFS) (p = 0.027 and p = 0.005, respectively). The Cox regression of RFS showed an HR of 0.332 (95%CI, 0.111–0.932) for ATRX expression >2.7 (p = 0.037), and an HR of 0.333 (95%CI, 0.140–0.790) for ZNRF3 expression >2 (p = 0.013). In conclusion, low protein expression of ATRX and ZNRF3 are negative prognostic markers of ACC; however, different cohorts should be evaluated to validate these findings.

A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence

BackgroundGenome-wide association studies (GWASs) have enriched the fields of genomics and drug development. Adrenocortical carcinoma (ACC) is a rare cancer with a bimodal age distribution and inadequate treatment options. Paediatric ACC is frequently associated with TP53 mutations, with particularly high incidence in Southern Brazil due to the TP53 p.R337H (R337H) germline mutation. The heterogeneous risk among carriers suggests other genetic modifiers could exist.MethodsWe analysed clinical, genotype and gene expression data derived from paediatric ACC, R337H carriers, and adult ACC patients. We restricted our analyses to single nucleotide polymorphisms (SNPs) previously identified in GWASs to associate with disease or human traits.ResultsA SNP, rs971074, in the alcohol dehydrogenase 7 gene significantly and reproducibly associated with allelic differences in ACC age-of-onset in both cohorts. Patients homozygous for the minor allele were diagnosed up to 16 years earlier. This SNP resides in a gene involved in the retinoic acid (RA) pathway and patients with differing levels of RA pathway gene expression in their tumours associate with differential ACC progression.ConclusionsThese results identify a novel genetic component to ACC development that resides in the retinoic acid pathway, thereby informing strategies to develop management, preventive and therapeutic treatments for ACC.

Exploring the role of systemic therapy in adult adrenocortical carcinoma: A single-center experience

Background: Adrenocortical carcinoma (ACC) is a rare malignancy with poor outcomes. Objectives: To analyze the clinicopathologic features, treatment patterns and outcomes of patients with ACC who received systemic therapy at our center. Patients and Methods: This was a retrospective study conducted in a tertiary cancer center in India. Patients aged 15 years and older who were diagnosed with ACC between January 2011 and December 2018 and received systemic therapy were included in this study. For tumor staging, the European Network for the Study of Adrenal Tumors (ENSAT) system was used. The outcomes were reported as progression-free survival (PFS) and overall survival (OS). All statistical calculations were performed using the SPSS statistical software for Windows version 20.0. Results: Out of the 106 patients with ACC, 54 who received systemic therapy were included in this study. The median age of the cohort was 43 years (range, 15–72); 32 (59.3%) were men. Five (9.2%) patients had ENSAT Stage II, 31 (57.4%) had Stage III, and 18 (33.3%) had Stage IV (metastatic) disease at baseline. The chemotherapy drugs used in the palliative setting included etoposide (E), doxorubicin (D), and cisplatin (P), with or without mitotane. The median OS was 140 months (95% confidence interval [CI], 38.2–241.8) for ENSAT Stage II patients; 43 months for Stage III patients (95% CI, 27.2–58.7); and 22 months (95% CI, 9.4–34.6) for Stage IV patients, P = 0.012. The median PFS for patients treated with etoposide and platin (EP) and etoposide, doxorubicin, and platin (EDP) regimens was similar at 7 months (95% CI, 0–14.9) and 6 months (95% CI: 0–14.6) (P = 0.633), respectively. The corresponding median OS was 20.9 months (95% CI, 11.7–30.2) and 13.0 months (95% CI, 2.1–23.8) (P = 0.454), respectively. The patients who received palliative intent mitotane had a median PFS of 13 months (95% CI, 0–26.3) and those who did not had a median PFS of 6 months (95% CI, 1.2–10.7) (P = 0.492). The corresponding median OS was 22.6 months (95% CI, 17.8–27.5) and 15.5 months (95% CI, 5.8–25.2) (P = 0.351), respectively. Grade 3 or higher toxicities were observed in 25% of the patients receiving EP chemotherapy and 76.9% receiving EDP chemotherapy (P = 0.013). Conclusions: The use of mitotane is limited in the real-world setting in view of the financial constraints. The results with palliative chemotherapy in patients with ACC continue to remain poor. Patients with ACC treated with EDP and EP protocols had similar survival, but the three-drug protocol was associated with higher toxicities.

A nomogram for individualized estimation of survival among adult patients with adrenocortical carcinoma after surgery: a retrospective analysis and multicenter validation study

BackgroundClinical outcome of adrenocortical carcinoma (ACC) varies because of its heterogeneous nature and reliable prognostic prediction model for adult ACC patients is limited. The objective of this study was to develop and externally validate a nomogram for overall survival (OS) prediction in adult patients with ACC after surgery.MethodsBased on the data from the Surveillance Epidemiology, and End Results (SEER) database, adults patients diagnosed with ACC between January 1988 and December 2015 were identified and classified into a training set, comprised of 404 patients diagnosed between January 2007 and December 2015, and an internal validation set, comprised of 318 patients diagnosed between January 1988 and December 2006. The endpoint of this study was OS. The nomogram was developed using a multivariate Cox proportional hazards regression algorithm in the training set and its performance was evaluated in terms of its discriminative ability, calibration, and clinical usefulness. The nomogram was then validated using the internal SEER validation, also externally validated using the Cancer Genome Atlas set (TCGA, 82 patients diagnosed between 1998 and 2012) and a Chinese multicenter cohort dataset (82 patients diagnosed between December 2002 and May 2018), respectively.ResultsAge at diagnosis, T stage, N stage, and M stage were identified as independent predictors for OS. A nomogram incorporating these four predictors was constructed using the training set and demonstrated good calibration and discrimination (C-index 95% confidence interval [CI], 0.715 [0.679–0.751]), which was validated in the internal validation set (C-index [95% CI], 0.672 [0.637–0.707]), the TCGA set (C-index [95% CI], 0.810 [0.732–0.888]) and the Chinese multicenter set (C-index [95% CI], 0.726 [0.633–0.819]), respectively. Encouragingly, the nomogram was able to successfully distinguished patients with a high-risk of mortality in all enrolled patients and in the subgroup analyses. Decision curve analysis indicated that the nomogram was clinically useful and applicable.ConclusionsThe study presents a nomogram that incorporates clinicopathological predictors, which can accurately predict the OS of adult ACC patients after surgery. This model and the corresponding risk classification system have the potential to guide therapy decisions after surgery.

DNA Methylation Profiling Reveals Prognostically Significant Groups in Pediatric Adrenocortical Tumors: A Report From the International Pediatric Adrenocortical Tumor Registry.

Pediatric adrenocortical carcinomas (ACCs) are aggressive; the overall survival of patients with ACCs is 40%-50%. Appropriate staging and histologic classification are crucial because children with incomplete resections, metastases, or relapsed disease have a dismal prognosis. The clinical course of pediatric adrenocortical tumors (ACTs) is difficult to predict using the current classification schemas, which rely on subjective microscopic and gross macroscopic variables. Recent advances in adult ACT studies have revealed distinct DNA methylation patterns with prognostic significance that have not been systematically interrogated in the pediatric population. We performed DNA methylation analyses on 48 newly diagnosed ACTs from the International Pediatric Adrenocortical Tumor Registry and 12 pediatric adrenal controls to evaluate for distinct methylation groups. Pediatric methylation data were also compared systematically with the adult ACC cohort from The Cancer Genome Atlas (TCGA). Two pediatric ACT methylation groups were identified and showed differences in selected clinicopathologic and outcome characteristics. The A1 group was enriched for CTNNB1 variants and unfavorable outcome. The A2 group was enriched for TP53 germline variants, younger age at onset, and favorable outcome. Pediatric ACT methylation groups were maintained when International Pediatric Adrenocortical Tumor Registry cohort data were combined with TCGA cohort data. The CpG-island hypermethylator phenotype characterizing the TCGA cohort was not identified in the pediatric patients. When methylome findings were combined with independent histopathologic review using the Wieneke criteria, a high-risk population was identified with uniform fatal outcome. Our results indicate DNA methylation analysis can enhance current diagnostic algorithms. A combination of methylation and histologic classification produced the strongest prediction model and may prove useful in future risk-adapted therapeutic trials.

Pediatric vs Adult Adrenocortical Carcinoma: Different Rate of Surgical Treatment and Patient Outcome

Pediatric vs Adult Adrenocortical Carcinoma: Different Rate of Surgical Treatment and Patient Outcome

Pediatric Mixed Functioning Adrenocortical Carcinoma: A Case Report and Review of Literature

Adrenocortical carcinoma (ACC) is a very rare disease in the pediatric age group. The clinic-biological profile, histopathological criteria of diagnosis, and staging of this disease in this age group are different from those of adult ACC. In this paper, we report a case of pediatric ACC presenting as Cushing syndrome that was managed with complete surgical excision. Through this case presentation, we highlight the sequential protocol of investigations and management in a child suspected of having ACC.

Diseases Predisposing to Adrenocortical Malignancy (Li-Fraumeni Syndrome, Beckwith-Wiedemann Syndrome, and Carney Complex).

Adrenocortical malignancies can occur in the context of several tumor predisposition syndromes.The Carney complex (CNC) is responsible for the majority of primary pigmented nodular adrenal diseases and is more rarely associated with adrenocortical carcinoma (ACC). Other core manifestations of CNC include cardiac and cutaneous myxomas, lentiginosis, somatotroph pituitary adenomas, Sertoli tumors, melanocytic schwannoma, and thyroid, breast, and bone tumors. CNC is mostly due to germline inactivating mutations of PRKAR1A.The majority of childhood ACC are related to genetic predisposition. The Beckwith-Wiedemann syndrome (BWS) is an overgrowth and tumor predisposition syndrome due to genetic or epigenetic alterations at the 11p15 locus. Classical tumor spectrum of BWS includes embryonal tumors and childhood ACC. The Li-Fraumeni syndrome (LFS) is a devastating tumor predisposition syndrome, due to germline inactivating mutations of TP53, and characterized by a high, various, and early-onset cancer risk. LFS spectrum includes premenopausal breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumor, and ACC, accounting for 50-80% of pediatric cases. Finally, germline predisposition affects up to 10% of adult ACC patients, mostly in part of LFS and Lynch syndrome.This chapter focuses on the diagnosis, screening, and management of adrenal tumors in part of these tumor predisposition syndromes.

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.