Cabozantinib monotherapy for advanced adrenocortical carcinoma: a single-arm, phase 2 trial.

BACKGROUND: Adrenocortical carcinoma is a rare malignancy with poor response to systemic chemotherapy. Mitotane is the only approved therapy for adrenocortical carcinoma. Cabozantinib is a multikinase inhibitor approved in multiple malignancies. This is the first prospective trial to explore the anti-tumour activity, safety, and pharmacokinetic profile of cabozantinib in patients with advanced adrenocortical carcinoma. METHODS: This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with advanced adrenocortical carcinoma was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients had histologically confirmed adrenocortical carcinoma, were not candidates for surgery with curative intent, had measurable disease, had an estimated life expectancy of at least 3 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 with adequate organ function. Patients who had used mitotane within 6 months of study participation were required to have a serum mitotane level of less than 2 mg/L. Patients were given oral cabozantinib 60 mg daily with the option of dose reduction to manage adverse events. The primary endpoint was progression-free survival at 4 months, assessed in all patients who received at least one dose of study drug per protocol. This study is registered with ClinicalTrials.gov, NCT03370718, and is now complete. FINDINGS: Between March 1, 2018, and May 31, 2021, we enrolled 18 patients (ten males and eight females), all of whom received at least one dose of study treatment. Of the 18 patients, eight (44%) had an ECOG performance status of 0, nine (50%) patients had a performance status of 1, and one (6%) patient had a performance status of 2. Median follow-up was 36·8 months (IQR 30·2-50·3). At 4 months, 13 (72·2%; 95% CI 46·5-90·3) of 18 patients had progression-free survival and median progression-free survival was 6 months (95% CI 4·3 to not reached). One patient remains on treatment. Treatment-related adverse events of grade 3 or worse occurred in 11 (61%) of 18 patients. The most common grade 3 adverse events were lipase elevation (three [17%] of 18 patients), elevated γ-glutamyl transferase concentrations (two [11%] patients), elevated alanine aminotransferase concentrations (two [11%] patients), hypophosphatemia (two [11%] patients), and hypertension (two [11%] patients). One (6%) of 18 patients had grade 4 hypertension. No treatment related deaths occurred on study. INTERPRETATION: Cabozantinib in advanced adrenocortical carcinoma showed promising efficacy with a manageable and anticipated safety profile. Further prospective studies with cabozantinib alone and in combination with immune checkpoint therapy are ongoing. FUNDING: Exelixis.

Venous thromboembolism in adrenocortical carcinoma: a retrospective analysis.

BACKGROUND: Venous thromboembolism (VTE) is a leading cause of death in patients with cancer. Limited data exist about VTE in patients with adrenocortical carcinoma (ACC). The primary objective of this study was to identify the prevalence of VTE in a cohort of patients with ACC. Secondary objectives were to determine the impact of VTE events on overall survival (OS) and to describe the characteristics of VTE in patients with ACC. PATIENTS AND METHODS: We retrospectively reviewed data from 289 patients with ACC cared for at a major referral center from February 2010 to June 2022. RESULTS: VTE prevalence was 18.7% (54 events). Thirty patients (55.6%) had pulmonary embolism (PE); 12 patients (22.2%) had deep vein thrombosis (DVT); and 12 patients (22.2%) had both PE and DVT. VTE occurred after ACC diagnosis in 50 patients (92.6%) including 44 patients (88%) with stage 3 or 4 ACC. VTEs were CTCAE grade ≤2 in 32 cases (59.3%), grade 3 in 17 (31.5%), and grade 4 in 2 (3.7%). Thirteen patients (24%) died within 6 months after VTE diagnosis, although there was no statistically significant association between VTE and overall survival. CONCLUSION: Despite the potential to underestimate the prevalence of VTEs, we found a high frequency of VTE events in patients with ACC. A majority of VTEs occurred in the context of advanced ACC and we observed high short-term mortality. Further studies are needed to validate our findings and investigate mechanisms associated with VTE in ACC.

Current Management Strategies and Outcomes in Children With Adrenocortical Carcinoma.

INTRODUCTION: Adrenocortical carcinoma (ACC) is a rare but aggressive pediatric endocrine tumor. However, there is no recent US national report on the management or outcomes of pediatric ACC. We aimed to examine the clinical characteristics, current management strategies, and outcomes of pediatric ACC. METHODS: In this retrospective National Cancer Database study between 2004 and 2019, children (<18 y) with ACC were included. Overall survival was examined by means of Kaplan-Meier method, log-rank tests, and Cox regression modeling. RESULTS: Seventy-eight children with ACC were included. The median age was 10 y, the median tumor size was 10.2 cm, and 35.9% had metastasis at diagnosis. Most patients underwent surgical treatment (84.6%), 56.4% received chemotherapy, and 7.7% received radiation. The 1-, 3-, and 5-y overall survival rates were 87.0%, 62.0%, and 60.1%, respectively. In unadjusted analysis, surgical treatment was associated with improved overall survival (log-rank test, P < 0.001). In multivariable Cox regression, metastasis at diagnosis was associated with inferior overall survival (hazard ratio: 2.72, 95% confidence interval: 1.15-6.40, P = 0.02), when adjusting for age, tumor size, receipt of surgical treatment, and chemotherapy. In patients with nonmetastatic ACC, increasing age was associated with inferior overall survival (hazard ratio: 1.12, 95% confidence interval: 1.00-1.24, P = 0.04), when adjusting for tumor size, receipt of surgical treatment, and chemotherapy. CONCLUSIONS: Most children with ACC in the USA undergo surgical treatment with about half of these also receiving chemotherapy. Metastasis at diagnosis was independently associated with inferior overall survival; in patients with nonmetastatic ACC, increasing age was independently associated with inferior overall survival.

Clinicopathological characteristics of adrenocortical carcinoma in the Kyushu-Okinawa area of Japan.

OBJECTIVE: Adrenocortical carcinoma is a rare condition, with limited comprehensive reports from Japan. This study aimed to review Japan's data on adrenocortical carcinoma by assessing information from 46 patients-with adrenocortical carcinoma across 10 Japanese university hospitals. METHODS: We conducted a retrospective multi-institutional analysis of the clinical characteristics of adrenocortical carcinoma in Japan. We evaluated data from 46 patients across 10 university hospitals over 10 years and analyzed the relationship between clinicopathological characteristics and overall survival. RESULTS: Five- and 10-year overall survival rates were 59% and 53%, respectively. Overall survival was significantly different among the tumor-node-metastasis system for adrenocortical carcinoma of the American Joint Committee on Cancer/International Union Against Cancer, with the worst prognosis in stage IV (p = 0.0044). In our cohort, neither the Weiss score nor the Ki-67 proliferation index correlated with overall survival. Adjuvant treatment did not yield improved overall survival, whereas resection of the primary tumor in stage IV disease was significantly associated with improved overall survival (p = 0.0262). Out of the cases evaluated for plasma hormones, plasma cortisol, aldosterone, testosterone, and DHEA-S levels were measured at 23%, 42%, 29%, and 62%, respectively, demonstrating higher levels than the upper normal limits. CONCLUSION: Patients with stage IV adrenocortical carcinoma had a poor prognosis; however, resection of the primary tumor in stage IV disease was associated with prolonged survival. The results of this study are expected to contribute to future treatment of adrenocortical carcinoma in Japan.

miRViz: a novel webserver application to visualize and interpret microRNA datasets.

MicroRNAs (miRNAs) are small non-coding RNAs that are involved in the regulation of major pathways in eukaryotic cells through their binding to and repression of multiple mRNAs. With high-throughput methodologies, various outcomes can be measured that produce long lists of miRNAs that are often difficult to interpret. A common question is: after differential expression or phenotypic screening of miRNA mimics, which miRNA should be chosen for further investigation? Here, we present miRViz (http://mirviz.prabi.fr/), a webserver application designed to visualize and interpret large miRNA datasets, with no need for programming skills. MiRViz has two main goals: (i) to help biologists to raise data-driven hypotheses and (ii) to share miRNA datasets in a straightforward way through publishable quality data representation, with emphasis on relevant groups of miRNAs. MiRViz can currently handle datasets from 11 eukaryotic species. We present real-case applications of miRViz, and provide both datasets and procedures to reproduce the corresponding figures. MiRViz offers rapid identification of miRNA families, as demonstrated here for the miRNA-320 family, which is significantly exported in exosomes of colon cancer cells. We also visually highlight a group of miRNAs associated with pluripotency that is particularly active in control of a breast cancer stem-cell population in culture.

MSI2 expression in adrenocortical carcinoma: Association with unfavorable prognosis and correlation with steroid and immune-related pathways.

Adrenocortical carcinoma (ACC) is a rare, but highly aggressive cancer of the adrenal cortex with a generally poor prognosis. Despite being rare, completely resected ACCs present a high risk of recurrence. Musashi-2 (MSI2) has recently been recognized as a potential prognostic biomarker and therapeutic target in many cancers. However, no studies have evaluated the clinical significance of MSI2 expression in ACC. Here, we addressed MSI2 expression and its association with ACC prognosis and clinicopathological parameters. MSI2 expression was analyzed in TCGA, GSE12368, GSE33371, and GSE49278 ACC datasets; and its correlation with other genes and immune cell infiltration were investigated by using the R2: Genomics Analysis and Visualization Platform and TIMER databases, respectively. Enrichment analysis was performed with the DAVID Functional Annotation Tool. Kaplan-Meier curves, log-rank tests, and Cox regression analyses were used to explore the prognostic role of MSI2 in ACC. Our findings demonstrated the potential value of MSI2 overexpression as an independent predictor of poor prognosis in patients with completely resected ACC (hazard ratio 6.715, 95% confidence interval 1.266 - 35.620, p =.025). In addition, MSI2 overexpression was associated with characteristics of unfavorable prognosis, such as cortisol excess (p = .002), recurrence (p =.003), and death (p =.015); positively correlated with genes related to steroid biosynthesis (p < .05); and negatively correlated with immune-related pathways (p < .05). Our findings demonstrate that MSI2 has value as a prognostic marker for completely resected ACC and reinforce the investigation of its role as a possible therapeutic target for patients with ACC.

Disparate Practice Patterns and Survival Outcomes: The Impact of Centralization of Cancer Care for Adrenocortical Carcinoma in the United States.

PURPOSE: Adrenocortical carcinoma is a rare but aggressive malignancy. While centralization of care to referral centers improves outcomes across common urological malignancies, there exists a paucity of data for low-incidence cancers. We sought to evaluate differences in practice patterns and overall survival in patients with adrenocortical carcinoma across types of treating facilities. MATERIALS AND METHODS: We identified all patients diagnosed with adrenocortical carcinoma from 2004-2016 in the National Cancer Database. The Kaplan-Meier method was used to evaluate overall survival and multivariable Cox regression analysis was used to investigate independent predictors of overall survival. The chi-square test was used to analyze differences in practice patterns. RESULTS: We identified 2,886 patients with adrenocortical carcinoma. Median overall survival was 21.8 months (95% CI 19.8-23.8). Academic centers had improved overall survival versus community centers on unadjusted Kaplan-Meier analysis (p <0.05) and had higher rates of adrenalectomy or radical en bloc resection (p <0.001), performed more open surgery (p <0.001), administered more systemic therapy (p <0.001) and had lower rates of positive surgical margins (p=0.03). On multivariable analysis, controlling for treatment modality, academic centers were associated with significantly decreased risk of death (HR 0.779, 95% CI 0.631-0.963, p=0.021). CONCLUSIONS: Treatment of adrenocortical carcinoma at an academic center is associated with improved overall survival compared to community programs. There are significant differences in practice patterns, including more aggressive surgical treatment at academic facilities, but the survival benefit persists on multivariable analysis controlling for treatment modality. Further studies are needed to identify the most important predictors of survival in this at-risk population.

Adrenal biopsy, as a diagnostic method, is associated with decreased overall survival in patients with T1/T2 adrenocortical carcinoma: A propensity score-matched analysis.

INTRODUCTION: The standard diagnosis for adrenocortical carcinoma (ACC) is clinical diagnosis (CD) based on radiographic and biochemical studies. Biopsy diagnosis (BD) is seldom required for the suspicion of secondary malignancy. We aim to study the impact of BD in the context of underlying T1/T2 ACC on overall survival (OS) compared with CD. METHODS: National Cancer Database (NCDB) for endocrine malignancies was utilized. Only patients with non-metastatic ACC, whose method of diagnosis and local disease extension were reported, and received a surgical adrenalectomy with curative intent were included. Patients were divided by disease stage into T1/T2, T3, and T4 groups. A propensity score match was applied to those with T1/T2 disease who received CD versus BD and the Kaplan-Meier method was used to compare OS. RESULTS: In total, 4000 patients with ACC were reported in the database, 1410 met selection criteria. Eight hundred and thirty patients had T1/T2, 365 had T3, and 162 had T4 ACC. Of patients with T1/T2 ACC, 742 (89.4%) received CD versus 88 (11.6%) with BD. A propensity score was calculated per a multivariable regression model with 79 patients matched from each group. Exact matching was applied for margin status and adjuvant therapies. Kaplan-Meier analysis showed a significant difference in median OS between CD versus BD patients in the matched data set (103.89 ± 15.65 vs. 54.93 ± 8.22 months; p = 0.001). In all comers, patients with T1/T2 ACC and BD had comparable median OS to that of patients with T3 ACC (52.21 ± 9.69 vs. 36.01 ± 3.33 months; p = 0.446). CONCLUSION: BD in T1/T2 ACC could be associated with disease upstaging and worse OS outcomes.

Clinical prognostic factors in pediatric adrenocortical tumors: A meta-analysis.

Pediatric adrenocortical tumors (ACT) are rare and sometimes aggressive malignancies, but there is no consensus on the outcome predictors in children. A systematic search of MEDLINE, SCOPUS, Web of Science, and the Cochrane Library for studies from 1994 to 2020 about pediatric ACT was performed. In 42 studies, 1006 patients, aged 0-18 years, were included. The meta-analyses resulted in the following predictors of better outcome: age <4 years (P < .00001), nonsecreting tumors (P = .004), complete surgical resection (P < .00001), tumor volume (P < .0001), tumor weight (P < .00001), tumor maximum diameter (P = .0009), and Stage I disease (P < .00001). Moreover, patients affected by Cushing syndrome showed a worse outcome (P < .0001). International prospective studies should be implemented to standardize clinical prognostic factors evaluation, together with pathological scores, in the stratification of pediatric ACT.

Positive Lymph Nodes in Adrenocortical Carcinoma: What Does It Mean?

BACKGROUND: The role of lymphadenectomy in adrenocortical carcinoma resection is controversial. Therefore, we conducted a population-based study to assess the association between positive lymph nodes (LN) and survival. METHODS: The Surveillance, Epidemiology, and End Results set of cancer registries were utilized. The associations between positive lymph nodes and tumor size, grade and laterality were assessed. Cancer specific survival (CSS) trends and factors affecting survival were analyzed. RESULTS: A total of 2170 adult patients were identified; 60% underwent resection. Among those resected, LN were examined in 23% and were positive in 25% of patients with LN examined. Patients with positive LN tended to have smaller tumors compared to those with negative LN (12 ± 5 vs 15 ± 11 cm, p = 0.02). The rate of positive LN was higher in right ACC, p = 0.03. Median overall CSS was 21 months, with significant differences between resection (42 months) and no resection (4 months), p < 0.01. Median CSS did not change over time when comparing ACC patients who underwent surgery before 2000, 2000-2009, and 2010-2016. On multivariable analysis including resection group, advanced age, grades III and IV, regional and distant stage, in addition to positive LN were associated with worse survival, p < 0.05. CONCLUSION: Lymphadenectomy is infrequently performed during ACC resection, and when performed, regional LN involvement tends to be associated with worse survival. Neoplasm size and grade were not associated with LN involvement and therefore, do not inform lymphadenectomy need. Further studies are needed to assess the indications for, and value of lymphadenectomy in ACC.

The underlying molecular mechanism and drugs for treatment in adrenal cortical carcinoma.

Purpose: The study aimed to predict and explore the possible clinical value and mechanism of genetic markers in adrenal cortical carcinoma using a bioinformatics analysis method. Methods: The RNA-seqs and miRNAs data were downloaded from TCGA database to identify the differentially expressed genes and differentially expressed miRNAs. The hub-genes were screened by building protein-protein interaction sub-networks with 12 topological analysis methods. We conducted the receiver operating characteristic curve to elevate the diagnostic value of hub-genes in distinguishing the death and alive groups. The survival analysis of hub-genes and key miRNAs were conducted using Kaplan-Meier curves. Furthermore, most significant small molecules were identified as therapeutic candidates for adrenal cortical carcinoma by the CMap analysis. Results: Compared to survival group, we found 475 up-regulated genes and 354 genes and the key pathways leading to the death of different ACC individual patients. Then we used 12 topological analysis methods to found the most possible 22 hub-genes. Among these hub-genes, nine hub-genes (C3, CXCL5, CX3CR1, GRM8, HCAR2, HTR1B, SUCNR1, PTGER3 and SSTR1) could be used to distinguish the death and survival groups for patients. We also revealed that mRNA expressions of 12 genes (C3, CXCL8, CX3CR1, GNAT3, GNGT1, GRM8, HCAR2, HTR1B, HTR1D, PTGER3, SSTR1 and SUCNR1) and four key miRNAs (hsa-mir-330, hsa-mir-489, hsa-mir-508 and hsa-mir-513b) were related to survival. Three most small molecules were identified (H-9, AZ-628 and phensuximide) as potential therapeutic drugs for adrenal cortical carcinoma. Conclusion: The hub-genes expression was significant useful in adrenal cortical carcinoma, provide new diagnostic, prognosis and therapeutic approaches for adrenal cortical carcinoma. Furthermore, we also explore the possible miRNAs involved in regulation of hub-genes.

Identification of NDRG Family Member 4 (NDRG4) and CDC28 Protein Kinase Regulatory Subunit 2 (CKS2) as Key Prognostic Genes in Adrenocortical Carcinoma by Transcriptomic Analysis.

BACKGROUND Adrenocortical carcinoma (ACC) is an aggressive cancer with heterogeneous outcomes. In this study, we aimed to investigate genomic and prognostic features of ACC. MATERIAL AND METHODS Clinical, pathologic, and transcriptomic data from 2 independent datasets derived from ACC samples (TCGA-ACC dataset, GEO-GSE76021 dataset) were collected. Weighted gene co-expression network analysis (WGCNA) and survival analyses were performed to identify prognostic genes. Pathway analysis was performed for mechanistic analysis. xCell deconvolution was performed for tumor microenvironment analysis. RESULTS In the TCGA-ACC cohort, WGCNA identified a prognostic module of 5408 genes. Differential expression analysis identified 1969 genes that differed in expression level between long-term and short-term survivors. Univariate Cox regression model analysis identified 8393 genes with prognostic value. The intersection of these gene sets included 820 prognostic genes. Similar protocols were performed for the GSE76021 dataset, and 5 candidate genes were identified. Further intersection of these genes finally identified NDRG4 and CKS2 as key prognostic genes. Multivariate Cox regression model analysis validated the prognostic value of NDRG4 (HR=0.61, 95% CI 0.46-0.80) and CKS2 (HR=2.52, 95% CI 1.38-4.60). Moreover, NDRG4 and CKS2 expression predicted survival in patients treated with mitotane (P<0.001). Further mechanism exploration found an association between CKS2 and DNA mismatch repair pathways. Moreover, NDRG4 positively correlated with CD8⁺ T cell infiltration, while CKS2 negatively correlated with it. CONCLUSIONS We identified NDRG4 and CKS2 expression as key prognostic genes in ACC, which may help in risk stratification of ACC. Moreover, a close relationship was found between CKS2 and mismatch repair pathways. Moreover, immune cell infiltration differed according to NDRG4 and CKS2 expression.

Neutrophil-Lymphocyte Ratio as a Prognostic Marker in Adrenocortical Carcinoma.

PURPOSE: The purpose of the present study was to analyze the impact of the neutrophil-lymphocyte ratio (NLR) on the long-term outcomes of patients with adrenocortical carcinoma (ACC). METHODS: This retrospective, single-institution study included 48 patients with the diagnosis of ACC. The primary outcomes of the study were differences in overall survival (OS) and disease-specific survival (DSS) with respect to the NLR level. RESULTS: Patients with ENSAT stage IV had higher levels of NLR compared to those with ENSAT stage I-III (5.7 (1.6-12.5) vs 3.3 (1.3-11); p = .01). A higher NLR was also observed among patients with cortisol-secreting tumors (4.6 (1.7-12.5) vs 2.8 (1.3-10.3); p = .003) and those with Ki-67 index >10% (4.3 (1.3-12.5) vs 2.6 (1.6-11.0); p = .005). With respect to survival, the univariate analysis revealed worse ACC-related survival (p = .02) and OS (p = .004) in patients with NLR >3.9 than in those with NLR ≤3.9. In addition, patients with NLR >3.9 had a higher Weiss score (p = .046), a higher Ki-67 index (p = .006) and a higher disease stage (p = .01) compared to patients with NLR ≤3.9. No differences between the groups were observed regarding excess glucocorticoid secretion. CONCLUSION: The study demonstrated that a higher NLR level in ACC patients was associated with unfavorable outcomes in terms of DSS and OS. These results indicate that NLR might be used as an additional marker in ACC risk stratification and identification of patients with the most adverse prognosis.

Autophagy-Related Proteins Are Differentially Expressed in Adrenal Cortical Tumor/Pheochromocytoma and Associated with Patient Prognosis.

The aim of this research was to evaluate the expression and concomitant implications of LC3A, LC3B, beclin-1, and p62, which are key components of autophagy in human adrenal gland tumors. Tissue microarray was made for 321 cases of adrenal gland tumor (adrenal cortical adenoma (ACA): 115, adrenal cortical carcinoma (ACC): 17, and pheochromocytoma (PCC): 189). Immunohistochemical staining was performed for beclin-1, p62, LC3A, and LC3B, and the results were compared with the patients' clinicopathologic parameters. LC3A, LC3B, beclin-1, and LC3B isolated single positive cells (ISPC) positivity rates were higher in PCC than in adrenal cortical tumor (ACT), whereas p62 positivity was lower in PCC than in ACT. The proportion of positive LC3B (ISPC) was higher in ACC than in ACA. In addition, the proportion of cells positive for p62 and LC3B (ISPC) was significantly higher in PCCs with a GAPP score of ≥3. In univariate Cox analysis, p62 positivity (p = 0.014) and the presence of p62 (ISPC) (p = 0.001) were associated with shorter disease-free survival in PCC. Moreover, p62 positivity was predictive of shorter overall survival (OS) in patients with PCC by multivariate analysis (relative risk, 6.240; 95% CI, 1.434-27.15; p = 0.015). Differences were found in the expression of autophagy-related proteins according to adrenal gland tumor types. Compared to ACT, the proportion of LC3A, LC3B, beclin-1, and LC3B (ISPC) positivity was higher in PCC, whereas p62 positivity was lower. Similarly, p62 positivity in PCC was associated with patient prognosis of OS.

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.

Stathmin 1 is highly expressed and associated with survival outcome in malignant adrenocortical tumours.

Adrenocortical carcinoma (ACC) is an aggressive endocrine cancer with few molecular predictors of malignancy and survival, especially in paediatric patients. Stathmin 1 (STMN1) regulates microtubule dynamics and has been involved in the malignant phenotype of cancer cells. Recently, it was reported that STMN1 is highly expressed in ACC patients, and STMN1 silencing reduces the clonogenicity and migration of ACC cell lines. However, the prognostic significance of STMN1 and its therapeutic potential remain undefined in ACC. In the present study, STMN1 mRNA levels were significantly higher (p < 0.05) in ACC patients, especially in an advanced stage, and correlated with BUB1B and PINK1 expression, the prognostic-related genes in ACC. In paediatric tumours, high STMN1 expression was observed in both adrenocortical carcinoma and adrenocortical adenoma patients. Among the adult malignant tumours, STMN1 level was an independent predictor of survival outcomes (overall survival: hazard ratio = 6.08, p = 0.002; disease-free survival: hazard ratio = 4.65, p < 0.0001). Paclitaxel, a microtubule-stabilizing drug, reduces the activation of STMN1 and significantly decreases cell migration and invasion in ACC cell lines and ACC cells from secondary cell culture (all p < 0.0001). In summary, STMN1 expression may be of great value to clinical and pathological findings in therapeutic trials and deserves future studies in ACC.

Comparative Performance of the 7th and 8th Editions of the American Joint Committee on Cancer Staging Manual for Adrenocortical Carcinoma.

BACKGROUND: The American Joint Committee on Cancer 8th edition staging manual for adrenocortical carcinoma (ACC) redefines T stage to include large vessel invasion (T4, previously undescribed) and restricts stage IV to those with distant metastases. We evaluated the prognostic power of the 8th edition. METHODS: Patients with ACC treated between January 1, 2000, and December 31, 2015, were identified. Overall survival (OS) was compared using Kaplan-Meier and Cox proportional hazard models. RESULTS: Of 290 patients evaluated, the change in T stage nomenclature impacted 13 (4.5%) who were previously categorized as T3; 61 had large vessel involvement but were already T4 based on invasion of adjacent organs. The restriction of stage IV to patients with distant metastases downstaged 41 (14.1%; T4N0M0 or T3-4N1M0) to stage III. In the 7th edition, the hazard ratio (HR) for death was similar between patients with stage II and III disease, with 5-year OS 66.7%, 54.4%, 57.2%, and 14.0% (stages I, II, III, and IV, respectively). In the 8th edition, stages I and II remain unchanged, with 5-year OS for stage III and IV 44.1% and 9.2%, respectively. The c-index for the 7th and 8th editions was similar (83.4 and 82.7, respectively). CONCLUSIONS: While 8th edition changes impact a relatively small proportion of ACC patients, they represent progress toward a common staging system that accurately reflects prognosis. In the 8th edition, the inclusion of patients with T4 tumors or nodal disease as stage III rather than IV results in improved stratification between stages II and III.

The role of immune checkpoint inhibitor therapy in advanced adrenocortical carcinoma revisited: review of literature.

PURPOSE: Adrenocortical carcinoma (ACC) is a rare disease with few therapeutic options. There is an urgency of new effective therapeutic options for these patients. The role of immune checkpoint inhibitors (ICI) in advanced ACC patients is still unclear. METHODS: We conducted a MEDLINE search using the following string: adrenocortical carcinoma and immunotherapy or checkpoint inhibitors. RESULTS: We found four case series comprising 10 patients, and four prospective studies totaling 115 patients. The response rate (RR) in the group of 10 patients was 1 complete response, 3 partial response (PR), 4 stable disease (SD), and 2 progressive disease (PD). The median progression-free survival (mPFS) ranged from 2 to 31 months and the median overall survival (mOS) ranged from 4.3 to 31 months. The results in the 115 patients from prospective trials was variable, the PR ranged from 6 to 23%, the SD ranged from 18 to 50% and overall disease control rate ranged from 30 to 64%. The mPFS reported varied from 1.8 to 2.6 months while the mOS varied from 10.6 to 24.9 months. There were five patients with sustained response for more than 24 months. The most common treatment-related adverse event (TRAE) was the increase in liver enzymes. No treatment-related deaths were reported. Better results in terms of RR and survival were observed in studies that used pembrolizumab. No predictive biomarker of response was found up to now. CONCLUSION: ICI, mainly pembrolizumab, is a potential therapeutic option, which is safe and associated with prolonged OS benefit, in selected patients with advanced ACC.

The outcome of childhood adrenocortical carcinoma in Egypt: A model from developing countries.

Adrenocortical carcinoma (ACC) is a rare, aggressive endocrine neoplasm. Complete surgical resection is the single most important treatment. Most available information has been learned from experience with its more frequent adult counterpart. In this study, we assessed the features and survival outcome of patients with ACC at Children's Cancer Hospital Egypt (CCHE). Patients diagnosed at CCHE between July 2007 and November 2016 were followed up on until November 2018. Patients with stages I and II were operated upon, while stages III and IV had received combinations of doxorubicin, etoposide, platinol, and mitotane (DEPM) beside the attempt to conduct surgery when feasible. Data belonging to 18 patients (7 men and 11 women) were analyzed; median age at diagnosis was 48.5 months. Sixteen patients had presented with secreting tumors. Six patients were diagnosed with stage I disease; four with stage II; three with stage III; and five with stage IV carcinoma. By the end of this study, 10 patients have survived; five-year overall survival of 66.3%. Surviving patients were all of stage I or II diseases and were all in remission. Seven patients who did not survive died due to tumor progression, while one patient died after chemotherapy. The prognosis of ACC is essentially dependent on a successful complete resection of the tumor and thus on the initial tumor stage. The mitotane and DEP protocols may help control tumor growth in the advanced stages for only short periods. Key pointsInitial stage and resectability are the main indicators of outcomes in adrenocortical carcinoma.Chemotherapeutic agents used in developed countries did not achieve the same outcomes.Further molecular-pharmacology differentiation is needed for various ethnic populations.

Prognostic significance of immunohistochemical markers in adrenocortical carcinoma.

Background: To present basic demographic and clinical characteristics of patients with adrenocortical carcinoma (ACC), to determine the overall survival rate and to analyze the results of immunohistochemical staining and its correlation with the length of survival.Material and methods: The study was conducted during the period between 1996 and 2010 and included 30 patients with ACC. Immunohistochemical staining (MMP9, melan A, inhibin, caltretinin, D2-40, synaptophysin and Ki-67) was performed.Results: ACC was diagnosed in 19 females and 11 men (1.7:1). The average age was 50.1 years. The median tumor size was 10 cm, the median weight 400 g. Majority of subjects had positive immunohistochemical staining for the markers of interest. Patients with any negative staining had shorter cancer-specific survival than ones with positive staining. According to the log-rank test results as well as according to the results of the univariate Cox analysis, negative staining for inhibin, D2-40 and synaptophysin and Ki-67 expression ≥7% were associated with poorer prognosis.Conclusions: The results of our study suggest that the absence of staining for some immunohistochemical markers and increased expression of Ki-67 are associated with a poorer prognosis and shorter survival of patients with ACC. Immunohistochemical markers may serve as a prognostic factor for ACC.