Thomas Kerkhofs

BACKGROUND: The clinical course of advanced adrenocortical carcinoma (ACC) is heterogeneous. Our study aimed primarily to refine and make headway in the prognostic stratification of advanced ACC. PATIENTS AND METHODS: Patients with advanced ENSAT ACC (stage III or stage IV) at diagnosis registered between 2000 and 2009 in the ENSAT database were enrolled. The primary end point was overall survival (OS). Parameters of potential prognostic relevance were selected. Univariate and multivariate analyses were carried out: model 1 'before surgery'; model 2 'post-surgery'. RESULTS: Four hundred and forty-four patients with advanced ENSAT ACC (stage III: 210; stage IV: 234) were analyzed. After a median follow-up of 55.2 months, the median OS was 24 months. A modified ENSAT (mENSAT) classification was validated: stage III (invasion of surrounding tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or >3 metastatic organs, including N, respectively). Two- or 5-year OS was 73%, 46%, 26% and 15% or 50%, 15%, 14% and 2% for stages III, IVa, IVb and IVc, respectively. In the multivariate analysis, mENSAT stages (stages IVa, IVb, or IVc, respectively) were significantly correlated with OS (P < 0.0001), as well as additional parameters: age ≥ 50 years (P < 0.0001), tumor- or hormone-related symptoms (P = 0.01 and 0.03, respectively) in model 1 but also the R status (P = 0.001) and Grade (Weiss >6 and/or Ki67 ≥ 20%, P = 0.06) in model 2. CONCLUSION: The mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC.

BACKGROUND: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC. METHODS: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs <4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of ACC), separately and in combination, using a reference standard of histopathology and follow-up investigations. With respect to imaging characteristics, we also assessed the diagnostic utility of increasing the unenhanced CT tumour attenuation threshold from the recommended 10 Hounsfield units (HU) to 20 HU. FINDINGS: Of 2169 participants recruited between Jan 17, 2011, and July 15, 2016, we included 2017 from 14 specialist centres in 11 countries in the final analysis. 98 (4·9%) had histopathologically or clinically and biochemically confirmed ACC. Tumours with diameters of 4 cm or larger were identified in 488 participants (24·2%), including 96 of the 98 with ACC (positive predictive value [PPV] 19·7%, 95% CI 16·2-23·5). For imaging characteristics, increasing the unenhanced CT tumour attenuation threshold to 20 HU from the recommended 10 HU increased specificity for ACC (80·0% [95% CI 77·9-82·0] vs 64·0% [61·4-66.4]) while maintaining sensitivity (99·0% [94·4-100·0] vs 100·0% [96·3-100·0]; PPV 19·7%, 16·3-23·5). A urine steroid metabolomics result indicating high risk of ACC had a PPV of 34·6% (95% CI 28·6-41·0). When the three tests were combined, in the order of tumour diameter, positive imaging characteristics, and urine steroid metabolomics, 106 (5·3%) participants had the result maximum tumour diameter of 4 cm or larger, positive imaging characteristics (with the 20 HU cutoff), and urine steroid metabolomics indicating high risk of ACC, for which the PPV was 76·4% (95% CI 67·2-84·1). 70 (3·5%) were classified as being at moderate risk of ACC and 1841 (91·3%) at low risk (negative predictive value 99·7%, 99·4-100·0). INTERPRETATION: An unenhanced CT tumour attenuation cutoff of 20 HU should replace that of 10 HU for exclusion of ACC. A triple test strategy of tumour diameter, imaging characteristics, and urine steroid metabolomics improves detection of ACC, which could shorten time to surgery for patients with ACC and help to avoid unnecessary surgery in patients with benign tumours. FUNDING: European Commission, UK Medical Research Council, Wellcome Trust, and UK National Institute for Health Research, US National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Radiological examination may unexpectedly reveal an adrenal mass. Current algorithms for differentiating between benign and malignant lesions mainly rely on size and densitometry on unenhanced CT, which have limited specificity. We examined the diagnostic value of urinary steroid profiling by gas chromatography/mass-spectrometry (GC/MS) in differentiating between benign and malignant adrenal tumors. A retrospective study in two referral centers for patients with adrenal disease was performed. All urinary steroid profiles ordered for evaluation of an adrenal tumor between January 2000 and November 2011 were examined. Patients were diagnosed with adrenal cortical carcinoma (ACC), adrenal cortical adenoma (ACA), or other adrenal mass. Results of hormonal measurements, imaging studies, pathology reports, and clinical outcome were retrieved from medical records. The diagnostic value of individual urinary steroid metabolites was determined by receiver operating characteristics analysis. Cut-off values were compared to reference values from an age and gender-standardized population of healthy controls. Eighteen steroid metabolites were excreted in significantly higher concentrations in patients with ACC (n = 27) compared to patients with ACA (n = 107) or other adrenal conditions (n = 18). Tetrahydro-11-deoxycortisol (THS) at a cut-off value of 2.35 μmol/24 h differentiated ACC from other adrenal disorders with 100% sensitivity and 99% specificity. Elevated urinary excretion of THS was associated with a very high sensitivity and specificity to differentiate between an ACC and a benign adrenal mass. Urinary steroid profiling might be a useful diagnostic test for the evaluation of patients with an adrenal incidentaloma.