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The human adrenal gland is a complex endocrine tissue. Studies on adrenal renewal have been limited to animal models or human foetuses. Enhancing our understanding of adult human adrenal homeostasis is crucial for gaining insights into the pathogenesis of adrenal diseases, such as adrenocortical tumours. Here, we present a comprehensive cellular genomics analysis of the adult human normal adrenal gland, combining single-nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland homeostasis. As expected, we identified primary cells of the various zones of the adrenal cortex and medulla, but we also uncovered additional cell types. They constitute the adrenal microenvironment, including immune cells, mostly composed of a large population of M2 macrophages, and new cell populations, including different subpopulations of vascular-endothelial cells and cortical-neuroendocrine cells. Utilizing spatial transcriptome and pseudotime trajectory analysis, we support evidence of the centripetal dynamics of adrenocortical cell maintenance and the essential role played by Wnt/ß-catenin, sonic hedgehog, and fibroblast growth factor pathways in the adult adrenocortical homeostasis. Furthermore, we compared single-nuclei transcriptional profiles obtained from six healthy adrenal glands and twelve adrenocortical adenomas. This analysis unveiled a notable heterogeneity in cell populations within the adenoma samples. In addition, we identified six distinct adenoma-specific clusters, each with varying distributions based on steroid profiles and tumour mutational status. Overall, our results provide novel insights into adrenal homeostasis and molecular mechanisms potentially underlying early adrenocortical tumorigenesis and/or autonomous steroid secretion. Our cell atlas represents a powerful resource to investigate other adrenal-related pathologies.
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Glândulas Suprarrenais , Homeostase , Transcriptoma , Humanos , Transcriptoma/genética , Glândulas Suprarrenais/metabolismo , Homeostase/genética , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Adulto , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologiaRESUMO
BACKGROUND: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Individuals with PBMAH and GIP-dependent Cushing's syndrome due to ectopic expression of the gastric inhibitory polypeptide receptor (GIPR) typically harbour inactivating KDM1A sequence variants. Primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess has never been encountered or studied. METHODS: We investigated a woman with a large, heterogeneous adrenal mass and severe ACTH-independent glucocorticoid and androgen excess, a biochemical presentation typically suggestive of adrenocortical carcinoma. The patient presented during pregnancy (22nd week of gestation) and reported an 18-month history of oligomenorrhoea, hirsutism, and weight gain. We undertook an exploratory study with detailed histopathological and genetic analysis of the resected adrenal mass and leukocyte DNA collected from the patient and her parents. RESULTS: Histopathology revealed benign macronodular adrenal hyperplasia. Imaging showed a persistently normal contralateral adrenal gland. Whole-exome sequencing of four representative nodules detected KDM1A germline variants, benign NM_001009999.3:c.136G>A:p.G46S and likely pathogenic NM_001009999.3:exon6:c.865_866del:p.R289Dfs*7. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA-sequencing of a representative nodule showed low/absent KDM1A expression and increased GIPR expression compared to 52 unilateral sporadic adenomas and four normal adrenal glands. LH Receptor (LHCGR) expression was normal. Sanger sequencing confirmed heterozygous KDM1A variants in both parents (father: p.R289Dfs*7; mother: p.G46S) who showed no clinical features suggestive of glucocorticoid or androgen excess. CONCLUSIONS: We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A.
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Adrenocortical carcinoma (ACC) is a rare yet devastating tumour of the adrenal gland with a molecular pathology that remains incompletely understood. To gain novel insights into the cellular landscape of ACC, we generated single-nuclei RNA sequencing (snRNA-seq) data sets from twelve ACC tumour samples and analysed these alongside snRNA-seq data sets from normal adrenal glands (NAGs). We find the ACC tumour microenvironment to be relatively devoid of immune cells compared to NAG tissues, consistent with known high tumour purity values for ACC as an immunologically "cold" tumour. Our analysis identifies three separate groups of ACC samples that are characterised by different relative compositions of adrenocortical cell types. These include cell populations that are specifically enriched in the most clinically aggressive and hormonally active tumours, displaying hallmarks of reorganised cell mechanobiology and dysregulated steroidogenesis, respectively. We also identified and validated a population of mitotically active adrenocortical cells that strongly overexpress genes POLQ, DIAPH3 and EZH2 to support tumour expansion alongside an LGR4+ progenitor-like or cell-of-origin candidate for adrenocortical carcinogenesis. Trajectory inference suggests the fate adopted by malignant adrenocortical cells upon differentiation is associated with the copy number or allelic balance state of the imprinted DLK1/MEG3 genomic locus, which we verified by assessing bulk tumour DNA methylation status. In conclusion, our results therefore provide new insights into the clinical and cellular heterogeneity of ACC, revealing how genetic perturbations to healthy adrenocortical renewal and zonation provide a molecular basis for disease pathogenesis.
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Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Regulação Neoplásica da Expressão Gênica , Microambiente Tumoral , Humanos , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/metabolismo , Microambiente Tumoral/genética , Análise de Célula Única , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Ligação ao Cálcio , Proteínas de MembranaRESUMO
BACKGROUND: Pheochromocytoma is associated with systemic inflammation, but the underlying mechanisms are unclear. Therefore, we investigated the relationship between plasma metanephrine levels and haematological parameters - as a surrogate of inflammation - in patients with pheochromocytoma and the influence of preoperative α-blockade treatment. DESIGN AND METHODS: We retrospectively studied 68 patients with pheochromocytoma who underwent adrenalectomy (median age 53 years, 64.7% females) and two control groups matched for age, sex, and body mass index (BMI): 68 patients with non-functioning adrenocortical tumors (NFAT) and 53 with essential hypertension (EAH). The complete blood count (CBC) and several inflammation-based scores [Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR), Systemic-Immune-Inflammation Index (SII), Prognostic-Nutrition Index (PNI)] were assessed in all patients and, in a subset of pheochromocytomas, after adrenalectomy (n=26) and before and after preoperative α-blockade treatment (n=29). RESULTS: A higher inflammatory state, as indicated by both CBC and inflammation-based scores, was observed in patients with pheochromocytoma compared to NFAT and EAH. Plasma metanephrine levels showed a positive correlation with NLR (r=0.4631), PLR (r=0.3174), SII (r=0.3709), and a negative correlation with LMR (r=0.4368) and PNI (r=0.3741), even after adjustment for age, sex, ethnicity, BMI and tumor size (except for PLR). After adrenalectomy, we observed a reduction in NLR (p=0.001), PLR (p=0.003), SII (p=0.004) and a concomitant increase in LMR (p=0.0002). Similarly, α-blockade treatment led to a reduction in NLR (p=0.007) and SII (p=0.03). CONCLUSIONS: Inflammation-based scores in patients with pheochromocytoma showed pro-inflammatory changes that correlated with plasma metanephrine levels and are ameliorated by adrenalectomy and α-blockade.
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OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. The aim of the study was to investigate the role of circulating cell-free DNA (ccfDNA)-related biomarkers (BMs) for prognostication and monitoring of ACC. DESIGN AND METHODS: We investigated 34 patients with ACC and 23 healthy subjects (HSs) as controls. Circulating cell-free DNA was extracted by commercial kits and ccfDNA concentrations were quantified by fluorimeter (BM1). Targeted sequencing was performed using a customized panel of 27 ACC-specific genes. Leucocyte DNA was used to discriminate somatic variants (BM2), while tumour DNA was sequenced in 22/34 cases for comparison. Serial ccfDNA samples were collected during follow-up in 19 ACC patients (median period 9 months) and analysed in relationship with standard radiological imaging. RESULTS: Circulating cell-free DNA concentrations were higher in ACC than HS (mean ± SD, 1.15 ± 1.56 vs 0.05 ± 0.05â ng/µL, P < .0001), 96% of them being above the cut-off of 0.146â ng/µL (mean HS + 2 SD, positive BM1). At ccfDNA sequencing, 47% of ACC showed at least 1 somatic mutation (positive BM2). A combined ccfDNA-BM score was strongly associated with both progression-free and overall survival (hazard ratio [HR] = 2.63; 95% CI, 1.13-6.13; P = .010, and HR = 5.98; 95% CI, 2.29-15.6; P = .0001, respectively). During disease monitoring, positive BM2 showed the best specificity (100%) and sensitivity (67%) to detect ACC recurrence or progress compared with BM1. CONCLUSION: ccfDNA-related BMs are frequently detected in ACC patients and represent a promising, minimally invasive tool to predict clinical outcome and complement surveillance imaging. Our findings will be validated in a larger cohort of ACCs with long-term follow-up.
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Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Ácidos Nucleicos Livres , Humanos , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/genética , Ácidos Nucleicos Livres/genética , Biomarcadores , DNA/genética , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/genética , Biomarcadores Tumorais/genéticaRESUMO
Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited treatment options. Polo-like kinase 1 (PLK1) is a promising drug target; PLK1 inhibitors (PLK1i) have been investigated in solid cancers and are more effective in TP53-mutated cases. We evaluated PLK1 expression in ACC samples and the efficacy of two PLK1i in ACC cell lines with different genetic backgrounds. PLK1 protein expression was investigated by immunohistochemistry in tissue samples and correlated with clinical data. The efficacy of rigosertib (RGS), targeting RAS/PI3K, CDKs and PLKs, and poloxin (Pol), specifically targeting the PLK1 polo-box domain, was tested in TP53-mutated NCI-H295R, MUC-1, and CU-ACC2 cells and in TP53 wild-type CU-ACC1. Effects on proliferation, apoptosis, and viability were determined. PLK1 immunostaining was stronger in TP53-mutated ACC samples vs wild-type (P = 0.0017). High PLK1 expression together with TP53 mutations correlated with shorter progression-free survival (P= 0.041). NCI-H295R showed a time- and dose-dependent reduction in proliferation with both PLK1i (P< 0.05at 100 nM RGS and 30 µM Pol). In MUC-1, a less pronounced decrease was observed (P< 0.05at 1000 nM RGS and 100 µM Pol). 100 nM RGS increased apoptosis in NCI-H295R (P< 0.001), with no effect on MUC-1. CU-ACC2 apoptosis was induced only at high concentrations (P < 0.05 at 3000 nM RGS and 100 µM Pol), while proliferation decreased at 1000 nM RGS and 30 µM Pol. CU-ACC1 proliferation reduced, and apoptosis increased, only at 100 µM Pol. TP53-mutated ACC cell lines demonstrated better response to PLK1i than wild-type CU-ACC1. These data suggest PLK1i may be a promising targeted treatment of a subset of ACC patients, pre-selected according to tumour genetic signature.
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The insulin-like growth factor 2 (IGF2) promotes cell growth by overactivating the IGF system in an autocrine loop in adrenocortical carcinomas (ACCs). The cytoskeleton protein filamin A (FLNA) acts as a repressor of IGF2 mitogenic signalling in ACC cells. The aims of this study were to test FLNA expression by immunohistochemistry in 119 ACCs and 26 adrenocortical adenomas (ACAs) and to evaluate its relationship with clinicopathological features and outcome in ACCs. We found that 71.4% of ACCs did not express FLNA, whereas FLNA absence was a rare event in ACAs (15.4%, p < 0.001 vs. ACCs). In addition, the expression of FLNA was associated with a less aggressive tumour behaviour in ACCs. Indeed, the subgroup of ACCs with high FLNA showed a lower ENSAT stage, Weiss score, and S-GRAS score compared to ACCs with low FLNA expression (p < 0.05). Moreover, patients with high FLNA had a longer overall survival than those with low FLNA (p < 0.05). In conclusion, our data suggest that FLNA may represent a "protective" factor in ACCs, and the integration of FLNA immunohistochemical expression in ACC tissues along with other clinical and molecular markers could be helpful to improve diagnostic accuracy and prognosis prediction in ACCs.
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Neoplasias do Córtex Suprarrenal , Adenoma Adrenocortical , Carcinoma Adrenocortical , Filaminas , Humanos , Neoplasias do Córtex Suprarrenal/diagnóstico , Adenoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/diagnóstico , Filaminas/genética , Filaminas/metabolismo , Transdução de Sinais , PrognósticoRESUMO
OBJECTIVE: Benign adrenocortical tumours are diagnosed in â¼5% of adults and are associated with cortisol excess in 30%-50% of cases. Adrenal Cushing's syndrome (CS) is rare and leads to multiple haematological alterations. However, little is known about the effects of the much more frequent mild autonomous cortisol secretion (MACS) on immune function. The aim of this study was to evaluate the haematological alterations in benign adrenocortical tumours with different degrees of cortisol excess. DESIGN AND METHODS: We investigated 375 patients: 215 with non-functioning adrenal tumours (NFAT), 138 with MACS, and 22 with CS. We evaluated the relationship between the degree of cortisol excess and full blood count as well as multiple inflammation-based scores, including the neutrophil-to-lymphocyte ratio (NLR), the lymphocyte-to-monocyte ratio (LMR), and the systemic immune-inflammation index (SII). RESULTS: We observed a gradual and significant increase of leucocytes, neutrophils, and monocytes across the spectrum of cortisol excess, from NFAT over MACS to CS. Neutrophil-to-lymphocyte ratio and SII were significantly higher in both MACS and CS when compared to NFAT (P < .001 and P = .002 for NLR and P = .006 and P = .021 for SII, respectively). Conversely, LMR was lower in MACS and CS than in NFAT (P = .01 and <.001, respectively) but also significantly lower in CS compared to MACS (P = .007). CONCLUSIONS: Neutrophil-to-lymphocyte ratio, SII, and LMR correlated with the degree of cortisol excess in benign adrenocortical tumours and were altered in patients with CS and MACS. These findings suggest that, similar to clinically overt CS, MACS also affects the immune function, potentially contributing to the MACS-associated comorbidities.
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Neoplasias do Córtex Suprarrenal , Neoplasias das Glândulas Suprarrenais , Síndrome de Cushing , Adulto , Humanos , Hidrocortisona , Síndrome de Cushing/diagnóstico , Estudos Retrospectivos , Neoplasias das Glândulas Suprarrenais/patologia , InflamaçãoRESUMO
OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with heterogeneous clinical outcomes. Recent studies proposed a combination of clinical/histopathological parameters (S-GRAS score) or molecular biomarkers (BMs) to improve prognostication. We performed a comparative analysis of DNA-based BMs by evaluating their added prognostic value to the S-GRAS score. DESIGN AND METHODS: A total of 194 formalin-fixed, paraffin-embedded (FFPE) ACC samples were analysed, including a retrospective training cohort (n = 107) and a prospective validation cohort (n = 87). Targeted DNA sequencing and pyrosequencing were used to detect somatic single-nucleotide variations in ACC-specific genes and methylation in the promoter region of paired box 5 (PAX5). The European Network for the Study of Adrenocortical Tumors (ENSAT) tumour stage, age, symptoms at presentation, resection status, and Ki-67 were combined to calculate S-GRAS. Endpoints were overall (OS), progression-free (PFS), and disease-free survival (DFS). Prognostic role was evaluated by multivariable survival analysis and their performance compared by Harrell's concordance index (C index). RESULTS: In training cohort, an independent prognostic role was confirmed at multivariate analysis for two DNA-based BMs: alterations in Wnt/ß-catenin and Rb/p53 pathways and hypermethylated PAX5 (both P< .05 for PFS and DFS, hazard ratio [HR] 1.47-2.33). These were combined to S-GRAS to obtain a combined (COMBI) score. At comparative analysis, the best discriminative prognostic model was COMBI score in both cohorts for all endpoints, followed by S-GRAS score (C index for OS 0.724 and 0.765, PFS 0.717 and 0.670, and DFS 0.699 and 0.644, respectively). CONCLUSIONS: Targeted DNA-based BM evaluated on routinely available FFPE samples improves prognostication of ACC beyond routinely available clinical and histopathological parameters. This approach may help to better individualise patient's management.
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Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Humanos , Carcinoma Adrenocortical/genética , Prognóstico , Estudos Retrospectivos , Neoplasias do Córtex Suprarrenal/genética , Intervalo Livre de DoençaRESUMO
CONTEXT: Pheochromocytomas are increasingly diagnosed in incidentally detected adrenal masses. However, the characteristics of incidental pheochromocytomas are unclear. OBJECTIVE: We aimed to assess the proportion and clinical, biochemical, radiological, genetic, histopathological, and follow-up characteristics of incidental pheochromocytomas. METHODS: A retrospective review was conducted of patients with pheochromocytoma seen between January 2010 and October 2022 at a large UK tertiary care center. The diagnosis was confirmed histologically or by the combined presence of increased plasma and/or urinary metanephrines (MN), indeterminate adrenal mass on cross-sectional imaging, and metaiodobenzylguanidine avidity. RESULTS: We identified 167 patients with pheochromocytoma; 144 (86.2%) underwent adrenalectomy, for 23 (13.8%) surgery was either awaited, deemed unsuitable due to frailty or other metastatic malignancy, or declined by the patients. Excluding pheochromocytomas diagnosed via screening genetically predisposed individuals (N = 20), 37 of 132 (28.0%) presented with adrenergic symptoms and/or uncontrolled hypertension, while 91 of 132 (69.0%) patients presented with an incidentally detected adrenal mass. Incidentally detected patients were older (median age 62 years) than those detected due to clinical suspicion (aged 42 years) or after genetic screening (aged 33 years) (all P < .05). Incidentally detected pheochromocytomas were smaller (median 42 mm) than tumors detected due to adrenergic symptoms/uncontrolled hypertension (60 mm), but larger than tumors identified by genetic screening (30 mm) (all P < .05). Increased MN excretion showed a similar pattern (symptomatic/uncontrolled hypertension > incidental > genetic screening) (all P < .05). Hereditary predisposition was detected in 20.4% of patients (incidental, 15.3%; symptomatic/uncontrolled hypertension, 42.9%). CONCLUSION: The majority of pheochromocytomas are diagnosed incidentally and have distinct clinical, radiological, biochemical, and genetic features. Their detection at older age but smaller size may point to a different underlying tumor biology.
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Neoplasias das Glândulas Suprarrenais , Hipertensão , Feocromocitoma , Humanos , Pessoa de Meia-Idade , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/genética , Feocromocitoma/diagnóstico , Feocromocitoma/epidemiologia , Feocromocitoma/genética , Hipertensão/epidemiologia , Adrenérgicos , Predisposição Genética para DoençaRESUMO
BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a heterogeneous prognosis, while adrenal metastasis from other primary cancers, including melanoma, may occur more frequently. ACC may rarely occur as part of familial cancer syndromes, but even in sporadic cases, a significant proportion of patients had other malignancies before or after diagnosis of ACC. Herein we present three cases where sporadic ACC was identified in patients with coexistent or previous history of melanoma. CASE DESCRIPTION: Patient 1 - A 37-yr-old man with a superficial spreading BRAF-positive melanoma was found to harbour a progressively growing left adrenal mass. Initially, he was suspected of having adrenal metastasis, but the histology after adrenalectomy confirmed ACC. Patient 2 - A 68-year-old man with a history of recurrent BRAF-positive melanoma was diagnosed with disseminated metastatic melanoma recurrence, including a rapidly enlarging left adrenal mass. Consequently, he underwent left adrenalectomy, and histology again confirmed ACC. Patient 3 - A 50-yr-old man was referred with histological diagnosis of metastatic ACC. He had a background history of pT1 melanoma. We undertook targeted sequencing of ACC tissue samples in all cases. Somatic variants were observed in the known driver genes CTNNB1 (Patient 1), APC and KMT2D (Patient 2), and APC and TP53 (Patient 3). Germline TP53 variants (Li-Fraumeni syndrome) were excluded in all cases. Retrospective review of our patient cohort in the last 21 years revealed a frequency of 0.5% of histologically diagnosed melanoma metastasis among patients referred for adrenal masses. On the other hand, 1.6% of patients with histologically confirmed ACC had a previous history of melanoma. CONCLUSION: Sporadic ACC can occur in the background of melanoma, even if adrenal metastasis might appear to be the most likely diagnosis. Coexistent primary adrenal malignancy should be considered and investigated for in all patients with a history of melanoma with suspicious adrenal lesions.
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Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Melanoma , Idoso , Humanos , Masculino , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/cirurgia , Melanoma/diagnóstico , Recidiva Local de Neoplasia , Proteínas Proto-Oncogênicas B-raf , Adulto , Melanoma Maligno CutâneoRESUMO
Treatment for advanced adrenocortical carcinoma (ACC) consists of mitotane alone or combined with etoposide, doxorubicin, and cisplatin (EDP). Although both therapies are widely used, markers of response are still lacking. Since inflammation-based scores have been proposed as prognostic factors in ACC, we aimed to investigate their role in predicting the response to first-line chemotherapy. We performed a retrospective analysis of patients with advanced ACC treated with mitotane monotherapy or EDP ± mitotane. Clinical parameters (tumour stage at diagnosis, resection status, Ki67, time from diagnosis to treatment start, performance status, plasma mitotane levels, time in mitotane target ≥ 80%, clinically overt cortisol hypersecretion), and pretreatment inflammation-based scores (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio, derived neutrophil-to-lymphocyte ratio) were investigated. The primary endpoints were overall survival (OS) and time-to-progression (TTP) from treatment initiation, the secondary endpoint was the best objective response to treatment. We included 90 patients (59% = women, median age = 51 years) treated with mitotane monotherapy (n = 40) or EDP ± mitotane (n = 50). In the mitotane monotherapy cohort, NLR ≥ 5 and PLR ≥ 190 predicted shorter OS (hazard ratio (HR): 145.83, 95% CI: 1.87-11,323.83; HR: 165.50, 95% CI: 1.76-15,538.04, respectively), remaining significant at multivariable analysis including clinical variables. NLR was also associated with shorter TTP (HR: 2.58, 95% CI: 1.28-5.20), but only at univariable analysis. Patients with NLR ≥ 5 showed a worse treatment response than those with NLR < 5 (P = 0.040). In the EDP ± mitotane cohort, NLR ≥ 5 predicted shorter OS (HR: 2.52, 95% CI: 1.30-4.88) and TTP (HR: 1.95, 95% CI: 1.04-3.66) at univariable analysis. In conclusion, inflammation-based scores, calculated from routinely measured parameters, may help predict response to chemotherapy in advanced ACC.
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Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Humanos , Feminino , Pessoa de Meia-Idade , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Mitotano/uso terapêutico , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/patologia , Estudos Retrospectivos , Inflamação/tratamento farmacológico , Prognóstico , Linfócitos/patologiaRESUMO
OBJECTIVE: Adrenal haemorrhage (AH) is an uncommon, usually incidental imaging finding in acutely unwell patients. AH has been reported during coronavirus disease 2019 (COVID-19) infection and following ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccination. The Society for Endocrinology (SfE) established a task force to describe the UK experience of COVID-19-related AH. DESIGN: A systematic literature review was undertaken. A survey was conducted through the SfE clinical membership to identify patients with COVID-19-related AH using a standardized data collection tool. RESULTS: The literature search yielded 25 cases of COVID-19-related AH (19 bilateral; 13 infection-related, and 12 vaccine-related). Eight UK centres responded to the survey with at least one case. A total of 18 cases were included in the descriptive study, including 11 from the survey and 7 UK-based patients from the systematic review. Seven patients (4 males; median age 53 (range 26-70) years), had infection-related AH (four bilateral). Median time from positive COVID-19 test to AH detection was 8 (range 1-30) days. Eleven cases of vaccine-related AH (eight bilateral) were captured (3 males; median age 47 (range 23-78) years). Median time between vaccination (nine Oxford-AstraZeneca and two Pfizer-BioNTech) and AH was 9 (range 2-27) days; 9/11 AH occurred after the first vaccine dose. Acute abdominal pain was the commonest presentation (72%) in AH of any cause. All 12 patients with bilateral AH and one patient with unilateral AH required glucocorticoid replacement. CONCLUSION: Adrenal haemorrhage with consequential adrenal insufficiency can be a complication of COVID-19 infection and vaccination. Adrenal function assessment is mandatory to avoid the potentially fatal consequences of unrecognized adrenal insufficiency.
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Insuficiência Adrenal , COVID-19 , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , ChAdOx1 nCoV-19 , COVID-19/complicações , Hemorragia , Reino Unido/epidemiologia , Estudos Multicêntricos como AssuntoRESUMO
Adrenal hemorrhage is an uncommon, underrecognized condition that can be encountered in several clinical contexts. Diagnosing adrenal hemorrhage is challenging due to its nonspecific clinical features. Therefore, it remains a diagnosis that is made serendipitously on imaging of acutely unwell patients rather than with prospective clinical suspicion. Adrenal hemorrhage can follow abdominal trauma or appear on a background of predisposing conditions such as adrenal tumors, sepsis, or coagulopathy. Adrenal hemorrhage is also increasingly reported in patients with COVID-19 infection and in the context of vaccine-induced immune thrombocytopenia and thrombosis. Unexplained abdominal pain with hemodynamic instability in a patient with a predisposing condition should alert the physician to the possibility of adrenal hemorrhage. Bilateral adrenal hemorrhage can lead to adrenal insufficiency and potentially fatal adrenal crisis without timely recognition and treatment. In this article, we highlight the clinical circumstances that are associated with higher risk of adrenal hemorrhage, encouraging clinicians to prospectively consider the diagnosis, and we share a diagnostic and management strategy.
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Doenças das Glândulas Suprarrenais , Neoplasias das Glândulas Suprarrenais , Insuficiência Adrenal , COVID-19 , Humanos , Estudos Prospectivos , COVID-19/complicações , Doenças das Glândulas Suprarrenais/complicações , Doenças das Glândulas Suprarrenais/diagnóstico , Hemorragia/diagnóstico , Hemorragia/etiologia , Hemorragia/terapia , Insuficiência Adrenal/complicações , Insuficiência Adrenal/diagnóstico , Neoplasias das Glândulas Suprarrenais/complicaçõesRESUMO
Summary: The spectrum of endocrine-related complications of COVID-19 infection is expanding; one of the most concerning of which is adrenal haemorrhage due to the risk of catastrophic adrenal crisis. In this study, we present a case that highlights the challenging management of a large, indeterminate unilateral adrenal mass during pregnancy and draws attention to a rare yet probably underestimated complication of COVID-19. During hospitalization for severe COVID-19 pneumonia, a 26-year-old woman was incidentally found to have a 12.5 cm heterogeneous left adrenal mass. Soon after the discovery, she became pregnant and upon referral, she was in the seventh week of gestation, without clinical or biochemical features of hormonal excess. The uncertainty of the diagnosis and the risks of malignancy and surgical intervention were discussed with the patient, and a period of radiological surveillance was agreed upon. An MRI scan performed 3 months later showed a size reduction of the adrenal lesion to 7.9 cm, which was against malignancy. A Doppler ultrasound showed a non-vascular, well-defined round lesion consistent with an adrenal haematoma, likely a complication of the recent COVID-19 infection. The multidisciplinary team recommended further radiological follow-up. The patient then spontaneously had miscarriage at 12 weeks gestation. Subsequent radiological surveillance showed a further size reduction of the adrenal lesion to 5.5 cm. The patient conceived again during follow-up, and the repeated Doppler ultrasound showed stable appearances of the adrenal mass, and thus, it was agreed to continue radiological monitoring after delivery. The pregnancy was uneventful, and the patient delivered a healthy baby. An MRI scan performed after delivery showed a stable but persistent lesion consistent with a likely underlying adrenal lesion. Learning points: Unilateral adrenal haemorrhage can occur as a complication of COVID-19 and should be considered in the differential diagnosis of heterogeneous adrenal masses if there is a history of recent infection. Management of large indeterminate adrenal masses during pregnancy poses several challenges and should be led by an experienced multidisciplinary team. Underlying adrenal tumours may trigger non-traumatic haemorrhages, especially if exacerbated by stressful illness.
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CONTEXT: Adrenocortical carcinoma (ACC) is a rare aggressive disease with heterogeneous prognoses. Previous studies identified hypermethylation in the promoter region of specific genes to be associated with poor clinical outcome. OBJECTIVE: Comparative analysis of promising hypermethylated genes as prognostic markers and evaluation of their added value to established clinical prognostic tools. DESIGN: We included 237 patients with ACCs. Tumor DNA was isolated from formalin-fixed paraffin-embedded (FFPE) samples. Targeted pyrosequencing was used to detect promoter region methylation in 5 preselected genes (PAX5, GSTP1, PYCARD, PAX6, G0S2). The prognostic role of hypermethylation pattern was compared with the Stage, Grade, Resection status, Age, Symptoms (S-GRAS) score. Primary endpoints were progression-free (PFS) and overall survival (OS), with disease-free (DFS) as secondary endpoint. RESULTS: A total of 27.9%, 13.9%, 49%, 49%, and 25.3% of cases showed hypermethylation in PAX5, GSTP1, PYCARD, PAX6, and G0S2, respectively. Hypermethylation in all individual genes-except GSTP1-was significantly associated with both PFS and OS-with hazard ratios (HR) between 1.4 and 2.3. However, only hypermethylation of PAX5 remained significantly associated with OS (Pâ =â 0.013; HRâ =â 1.95, 95% CI, 1.2-3.3) in multivariable analysis. A model for risk stratification was developed, combining PAX5 methylation status and S-GRAS groups, showing improved prognostic performance compared to S-GRAS alone (Harrell's C index: OSâ =â 0.751, PFSâ =â 0.711, DFSâ =â 0.688). CONCLUSIONS: This study demonstrated that hypermethylation in PAX5 is associated with worst clinical outcome in ACC, even after accounting for S-GRAS score. Assessing methylation in FFPE material is straightforward in the clinical setting and could be used to improve accuracy of prognostic classification, enabling the direction of personalized management.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Metilação de DNA , Formaldeído , Glutationa S-Transferase pi , Humanos , Inclusão em Parafina , PrognósticoRESUMO
Non-coding RNAs (ncRNAs) are a type of genetic material that do not encode proteins but regulate the gene expression at an epigenetic level, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The role played by ncRNAs in many physiological and pathological processes has gained attention during the last few decades, as they might be useful in the diagnosis, treatment and management of several human disorders, including endocrine and oncological diseases. Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine cancer, still characterized by high mortality and morbidity due to both endocrine and oncological complications. Despite the rarity of this disease, recently, the role of ncRNA has been quite extensively evaluated in ACC. In order to better explore the role of the ncRNA in human ACC, this review summarizes the current knowledge on ncRNA dysregulation in ACC and its potential role in the diagnosis, treatment, and management of this tumor.
Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , MicroRNAs , RNA Longo não Codificante , Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/metabolismoRESUMO
BACKGROUND: The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing). METHODS: We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800-0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50-138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants. FINDINGS: Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53-68]; median follow-up 7·0 years [IQR 4·7-10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93-9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001). INTERPRETATION: Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma. FUNDING: Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino.
Assuntos
Adenoma , Neoplasias das Glândulas Suprarrenais , Hipertensão , Adenoma/complicações , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/epidemiologia , Estudos de Coortes , Dexametasona , Feminino , Humanos , Hidrocortisona , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Major technological advances in genomics have made it possible to identify critical genetic alterations in cancer, rendering oncology well along the path to personalised cancer medicine [...].