Adrenocortical carcinoma: Diagnosis, prognostic classification and treatment of localized and advanced disease.

Adrenocortical carcinoma (ACC) is a rare cancer with an estimated incidence of 0.7 to 2.0 cases per 1 million population per year in the United States. It is an aggressive cancer originating in the cortex of the adrenal gland with a poor prognosis. The 5-year survival rate is less than 15% among patients with metastatic disease. In this article, we review the epidemiology and pathogenesis of ACC, the diagnostic procedures, the prognostic classification of ACC, and the treatment options from localized and resectable forms to advanced disease detailing recent therapeutic developments such as immunotherapy and molecularly targeted therapy.

Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study.

BACKGROUND: Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence. METHODS: ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete. FINDINGS: Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30-1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION: Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment. FUNDING: AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health.

[French recommendations for malignant pheochromocytomas and paragangliomas by the national ENDOCAN-COMETE network]. / Recommandations du réseau national ENDOCAN-COMETE pour la prise en charge des phéochromocytomes et paragangliomes métastatiques.

Pheochromocytomas and paragangliomas are rare neuroendocrine tumors, developed respectively in the adrenal medulla and in extra-adrenal locations. Their malignancy is defined by the presence of distant metastases. Forty percent of them are inherited and can be part of different hereditary syndromes. Their management is ensured in France by the multidisciplinary expert centers of the ENDOCAN-COMETE national network "Cancers of the Adrenal gland", certified by the National Cancer Institute and discussed within multidisciplinary team meetings. The diagnostic and therapeutic work-up must be standardized, based on an expert analysis of clinical symptoms, hormonal biological secretions, genetics, morphological and specific metabolic imaging. In the context of a heterogeneous survival sometimes beyond seven to ten years, therapeutic intervention must be justified. This is multidisciplinary and relies on surgery, interventional radiology, external or internal radiotherapy and medical treatments such as sunitinib or dacarbazine and temodal chemotherapy. The personalized approach based on functional imaging fixation status and genetics is progressing despite the extreme rarity of this disease.

Laparoscopic or Open Adrenalectomy for Stage I-II Adrenocortical Carcinoma: A Retrospective Study.

Surgical resection of adrenocortical carcinoma (ACC) is the only curative treatment. Even in localized (I-II) stages, open adrenalectomy (OA) is the gold standard, though laparoscopic adrenalectomy (LA) can be proposed in selected patients. Despite the postoperative benefits of LA, its role in the surgical management of patients with ACC remains controversial regarding oncologic outcomes. The aim of this retrospective study was to compare the outcomes of patients with localized ACC submitted to LA or OA in a referral center from 1995 to 2020. Among 180 consecutive patients operated on for ACC, 49 presented with localized ACC (19 LA and 30 OA). Baseline characteristics were similar between groups, except for tumor size. Kaplan-Meier estimates of 5-year overall survival were similar in both groups (p = 0.166) but 3-year disease-free survival was in favor of OA (p = 0.020). Though LA could be proposed in highly selected patients, OA should still be considered the standard approach in patients with known or suspected localized ACC.

Outcome of adrenocortical carcinoma patients included in early phase clinical trials: Results from the French network ENDOCAN-COMETE.

BACKGROUND: At metastatic stage, treatment of adrenocortical carcinoma (ACC) relies in first line on mitotane therapy, combination of mitotane with locoregional therapies or cisplatin-based chemotherapy according to initial presentation. In second line, ESMO-EURACAN recommendations favour enrolment of patients in clinical trials investigating experimental therapies. However, the benefit of this approach remains unknown. METHODS: The aim of our retrospective study was to analyse the inclusion and outcomes of all patients of the French cohort ENDOCAN-COMETE included in early clinical trials between 2009 and 2019. RESULTS: Of the 141 patients for whom a local or national multidisciplinary tumour board recommended, as first choice, to look for clinical trial, 27 patients (19%) were enroled in 30 early clinical trials. Median progression-free survival (PFS) was 3.02 months (95% confidence interval [95% CI]; 2.3-4.6) and median overall survival (OS) was 10.2 months (95% CI; 7.13-16.3) while the best response, evaluable in 28 of 30 trial participants according to RECIST 1.1 criteria, was partial response for 3 patients (11%) stable disease for 14 patients (50%) and progressive disease for 11 patients (39%), resulting in a disease control rate of 61%. Median growth modulation index (GMI) in our cohort was 1.32, with a significantly prolonged PFS in 52% of the patients compared to the previous line. The Royal Marsden Hospital (RMH) prognostic score was not associated with OS in this cohort. CONCLUSION: Our study suggests that patients with metastatic ACC benefit from inclusion in early clinical trials in second line. As recommended, if a clinical trial is available, it should be the first choice for suitable patients.

[Guidelines of the French National ENDOCAN-COMETE, Association of Endocrine Surgery, Society of Urology for the management of adrenocortical carcinoma]. / Recommandations conjointes du réseau National ENDOCAN-COMETE, de l'Association francophone de chirurgie endocrinienne et de la Société française d'urologie pour la prise en charge du carcinome corticosurrénalien.

The adrenocortical carcinoma (ACC) is a primary malignant tumor developed from the adrenal cortex, defined by a Weiss score≥3. Its prognosis is poor and depends mainly on the stage of the disease at diagnosis. Care is organized in France by the multidisciplinary expert centers of the national ENDOCAN-COMETE "Adrenal Cancers" network, certified by the National Cancer Institute. This document updates the guidelines for the management of ACC in adults based on the most robust data in the literature. It's divided into 11 chapters: (1) circumstances of discovery; (2) pre-therapeutic assessment; (3) diagnosis of ACC; (4) oncogenetics; (5) prognostic classifications; (6) treatment of hormonal hypersecretion; (7) treatment of localized forms; (8) treatment of relapses; (9) treatment of advanced forms; (10) follow-up; (11) the particular case of ACC and pregnancy. R0 resection of all localized ACC remains an unmet need and it must be performed in expert centers. Flow-charts for the therapeutic management of localized ACC, relapse or advanced ACC are provided. It was written by the experts from the national ENDOCAN-COMETE network and validated by all French Societies involved in the management of these patients (endocrinology, medical oncology, endocrine surgery, urology, pathology, genetics, nuclear medicine, radiology, interventional radiology).

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

PURPOSE OF THE REPORT: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Real-life efficacy and predictors of response to immunotherapy in pituitary tumors: a cohort study.

Objective: After temozolomide failure, no evidence-based treatment is available for pituitary carcinomas (PCs) and aggressive pituitary tumors (APTs). To date, only 12 cases treated with immune-checkpoint inhibitors (ICIs) have been published, showing encouraging efficacy. Predictive factors of response are lacking. Here, we aimed to assess the real-life efficacy and predictors of response to ICIs in PCs and APTs. Design and methods: This study is a multicentric, retrospective, observational cohort study, including all PCs and APTs treated with ICIs in France up to March 2022. PD-L1 immunohistochemistry and CD8+ T cell infiltration were evaluated centrally. Results: Six PCs (four corticotroph and two lactotroph) and nine APTs (five corticotroph and four lactotroph) were included. The real-life efficacy of ICIs was lower than previously published data. Three corticotroph tumors (33.3%) showed partial response, one (11.1%) stable disease, while five (55.6%) progressed. One lactotroph tumor (16.7%) showed partial response, one (16.7%) stable disease, while four (66.7%) progressed. PCs responded far better than APTs, with 4/6 PCs showing partial response compared to 0/9 APTs. Corticotroph tumors responded slightly better than lactotroph tumors. In the four responsive corticotroph tumors, PD-L1 staining was negative and CD8+ T cell infiltration attained a maximum of 1% in the tumor center. Conclusions: Confirmation of the presence or absence of metastases is necessary before starting ICIs. After temozolomide failure, ICIs appear as a good therapeutic option for PCs, especially for corticotroph carcinomas. Negative PD-L1 staining and very low CD8+ T cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Significance statement: This is the first study to assess the real-life efficacy of ICIs in pituitary carcinomas (PCs) and aggressive pituitary tumors. We also assessed potential predictors of response and are the first to assess the predictive value of CD8+ cell infiltration. We identified the tumor type as a major predictor, ICIs proving far more effective in treating PCs. Our study provides evidence that ICIs are a good option after temozolomide failure for PCs (four of six responded), especially for corticotroph carcinomas (three of four responded). We also provide evidence that negative PD-L1 staining and very low CD8+ cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Moreover, our findings point toward the need to systematically perform extension workup before starting ICIs.

Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients.

Objective: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a heterogeneous disease characterized by adrenal macronodules and variable levels of cortisol excess, with not clearly established clinical diagnostic criteria. It can be caused by ARMC5 germline pathogenic variants. In this study, we aimed to identify predictive criteria for ARMC5 variants. Methods: We included 352 consecutive index patients from 12 European centers, sequenced for germline ARMC5 alteration. Clinical, biological and imaging data were collected retrospectively. Results: 52 patients (14.8%) carried ARMC5 germline pathogenic variants and showed a more distinct phenotype than non-mutated patients for cortisol excess (24-h urinary free cortisol 2.32 vs 1.11-fold ULN, respectively, P < 0.001) and adrenal morphology (maximal adrenal diameter 104 vs 83 mm, respectively, P < 0.001) and were more often surgically or medically treated (67.9 vs 36.8%, respectively, P < 0.001). ARMC5-mutated patients showed a constant, bilateral adrenal involvement and at least a possible autonomous cortisol secretion (defined by a plasma cortisol after 1 mg dexamethasone suppression above 50 nmol/L), while these criteria were not systematic in WT patients (78.3%). The association of these two criteria holds a 100% sensitivity and a 100% negative predictive value for ARMC5 pathogenic variant. Conclusion: We report the largest series of index patients investigated for ARMC5 and confirm that ARMC5 pathogenic variants are associated with a more severe phenotype in most cases. To minimize negative ARMC5 screening, genotyping should be limited to clear bilateral adrenal involvement and autonomous cortisol secretion, with an optimum sensitivity for routine clinical practice. These findings will also help to better define PBMAH diagnostic criteria.

Transcriptome in paraffin samples for the diagnosis and prognosis of adrenocortical carcinoma.

Design: Molecular classification is important for the diagnosis and prognosis of adrenocortical tumors (ACT). Transcriptome profiles separate adrenocortical adenomas 'C2' from carcinomas, and identify two groups of carcinomas 'C1A' and 'C1B', of poor and better prognosis respectively. However, many ACT cannot be profiled because of improper or absent freezing procedures, a mandatory requirement so far. The main aim was to determine transcriptome profiles on formalin-fixed paraffin-embedded (FFPE) samples, using the new 3'-end RNA-sequencing technology. A secondary aim was to demonstrate the ability of this technique to explore large FFPE archives, by focusing on the rare oncocytic ACT variants. Methods: We included 131 ACT: a training cohort from Cochin hospital and an independent validation cohort from Wuerzburg hospital. The 3' transcriptome was generated from FFPE samples using QuantSeq (Lexogen, Vienna, Austria) and NextSeq500 (Illumina, San Diego, CA, USA). Results: In the training cohort, unsupervised clustering identified three groups: 'C1A' aggressive carcinomas (n = 28, 29%), 'C1B' more indolent carcinomas (n = 28, 29%), and 'C2' adenomas (n = 39, 41%). The prognostic value of FFPE transcriptome was confirmed in the validation cohort (5-year OS: 26% in 'C1A' (n = 26) and 100% in 'C1B' (n = 10), P = 0.003). FFPE transcriptome was an independent prognostic factor in a multivariable model including tumor stage and Ki-67 (OS HR: 7.5, P = 0.01). Oncocytic ACT (n = 19) did not form any specific cluster. Oncocytic carcinomas (n = 6) and oncocytic ACT of uncertain malignant potential (n = 4) were all in 'C1B'. Conclusions: The 3' RNA-sequencing represents a convenient solution for determining ACT molecular class from FFPE samples. This technique should facilitate routine use and large retrospective studies.

Adrenal Mass Characterization in the Era of Quantitative Imaging: State of the Art.

Detection and characterization of adrenal lesions have evolved during the past two decades. Although the role of imaging in adrenal lesions associated with hormonal secretion is usually straightforward, characterization of non-functioning adrenal lesions may be challenging to confidently identify those that need to be resected. Although many adrenal lesions can be readily diagnosed when they display typical imaging features, the diagnosis may be challenging for atypical lesions. Computed tomography (CT) remains the cornerstone of adrenal imaging, but other morphological or functional modalities can be used in combination to reach a diagnosis and avoid useless biopsy or surgery. Early- and delayed-phase contrast-enhanced CT images are essential for diagnosing lipid-poor adenoma. Ongoing studies are evaluating the capabilities of dual-energy CT to provide valid virtual non-contrast attenuation and iodine density measurements from contrast-enhanced examinations. Adrenal lesions with attenuation values between 10 and 30 Hounsfield units (HU) on unenhanced CT can be characterized by MRI when iodinated contrast material injection cannot be performed. 18F-FDG PET/CT helps differentiate between atypical benign and malignant adrenal lesions, with the adrenal-to-liver maximum standardized uptake value ratio being the most discriminative variable. Recent studies evaluating the capabilities of radiomics and artificial intelligence have shown encouraging results.

Recurrence of a Pheochromocytoma With TNEM127 Mutation Negative on 18F-FDOPA and 18F-FDG but Positive on 123I-MIBG and 68Ga-DOTATOC Imaging.

ABSTRACT: We report the case of a 75-year-old woman with liver metastasis as a recurrence of a pheochromocytoma resected 10 years ago, with a rare germline mutation in transmembrane protein 127, falsely negative on 18F-FDOPA and 18F-FDG PET/CT scans but strongly positive on 123I-MIBG scintigraphy and on 68Ga-DOTATOC PET/CT. Functional imaging has a key role in diagnosis of pheochromocytoma and paraganglioma, especially 18F-FDOPA shows very high sensitivity and specificity. However, 18F-FDOPA might be falsely negative in some of these tumors, depending on specific mutations, and thus MIBG or 68Ga-DOTATOC imaging could be an alternative.

Progression of Vertebral Fractures in Patients with Adrenocortical Carcinoma Undergoing Mitotane Therapy.

CONTEXT: Patients with adrenocortical carcinoma (ACC) are frequently on mitotane therapy for a long time period. The drug exerts adrenolytic activity requiring glucocorticoid supplementation, which can be potentially detrimental for bone. OBJECTIVE: To explore whether mitotane with/without chemotherapy is associated with an increased proportion of morphometric vertebral fractures (VFs) in ACC patients. Secondary objectives were proportion of patients with VF progression, or worsening of the spinal deformity index (SDI) during mitotane therapy; and to explore predictive factors of VF progression and a prognostic role of VF progression. METHODS: Multicenter, retrospective cohort study of patients with ACC who received mitotane alone or in association to chemotherapy, recruited from January 2010 to January 2020 in 2 reference centers in Italy and France. RESULTS: A significant increase in the frequency of VFs before and after mitotane therapy was seen both in Italian (28.3% vs 47.8%, P = .04) and French (17.8% vs 35.6%, P = .04) series. VF progression was observed in 39.1%, and 28.9% of patients, respectively. Baseline VFs and increased patient body mass index, but not the dose of cortisol supplementation, showed an independent association with VF progression at multivariate analysis. Among the 72 advanced ACC patients, progression of VFs was associated with a poorer survival. CONCLUSION: The administration of mitotane with/without chemotherapy in ACC patients impairs bone health independently from cortisol supplementation. Appropriate preventive measures to decrease the fracture risk should be implemented in these patients.

KDM1A inactivation causes hereditary food-dependent Cushing syndrome.

PURPOSE: This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS. METHODS: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing). RESULTS: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10-12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS. CONCLUSION: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management.

What Is the Optimal Duration of Adjuvant Mitotane Therapy in Adrenocortical Carcinoma? An Unanswered Question.

A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence.

Preoperative Detection of Liver Involvement by Right-Sided Adrenocortical Carcinoma Using CT and MRI.

The major prognosis factor of adrenocortical carcinoma (ACC) is the completeness of surgery. The aim of our study was to identify preoperative imaging features associated with direct liver involvement (DLI) by right-sided ACC. Two radiologists, blinded to the outcome, independently reviewed preoperative CT and MRI examinations for eight signs of DLI, in patients operated for right-sided ACC and retrospectively included from November 2007 to January 2020. DLI was confirmed using surgical and histopathological findings. Kappa values were calculated. Univariable and multivariable analyses were performed by using a logistic regression model. Receiver operating characteristic (ROC) curves were built for CT and MRI. Twenty-nine patients were included. Seven patients had DLI requiring en bloc resection. At multivariable analysis, focal ACC bulge was the single independent sign associated with DLI on CT (OR: 60.00; 95% CI: 4.60-782.40; p < 0.001), and ACC contour disruption was the single independent sign associated with DLI on MRI (OR: 126.00; 95% CI: 6.82-2328.21; p < 0.001). Both signs were highly reproducible, with respective kappa values of 0.85 and 0.91. The areas under ROC curves of MRI and CT models were not different (p = 0.838). Focal ACC bulge on CT and ACC contour disruption on MRI are independent and highly reproducible signs, strongly associated with DLI by right-sided ACC on preoperative imaging. MRI does not improve the preoperative assessment of DLI by comparison with CT.