Increased adrenal steroidogenesis and suppressed corticosteroid responsiveness in critical COVID-19.

BACKGROUND: The effect of coronavirus disease 2019 (COVID-19) on adrenal endocrine metabolism in critically ill patients remains unclear. This study aimed to investigate the alterations in adrenal steroidogenic activity, elucidate underlying mechanisms, provide in situ histopathological evidence, and examine the clinical implications. METHODS: The comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls were performed, excluding patients previously treated with glucocorticoids. SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity and responsive genes of mineralocorticoid and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness. FINDINGS: The demographic characteristics of COVID-19 patients were comparable with those of controls. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors and their responsive genes in vital tissues were markedly reduced in patients with critical COVID-19. INTERPRETATION: Critical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with increased inflammation, enhanced differentiation and elevated dual-ZG/ZF identity cells, alongside suppressed corticosteroid responsiveness. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of the adrenal axis and corticosteroid sensitivity.

Vascular endothelial growth factor and endocan expression in adrenal cortical tumors and their relationship with histopathological prognostic parameters.

The aim of this study was to determine the tissue expressions of vascular endothelial growth factor (VEGF) and endocan in adrenal cortical tumors and the factors associated with them. The study included 6 subjects with adrenocortical adenoma (ACA), 7 subjects with adrenocortical carcinoma (ACC), and 13 control subjects with a normal adrenal cortex. The status of VEGF and endocan expression was determined by the proportions of cells staining on a scale ranging from negative (not staining at all) to strongly positive. VEGF expression was detected in 1 (16.7%) of 6 subjects in the ACA group and in 6 (85.7%) of 7 subjects in the ACC group. VEGF expression was not detected in any of the subjects in the control group. Endocan expression was detected in 6 (100%) of 6 subjects in the ACA group and in 7 (100%) of 7 subjects in the ACC group, while it was detected in only 4 (30.7%) of 13 subjects in the control group. VEGF was expressed with a high frequency in subjects with ACC and with a low frequency in subjects with ACA, but it was not expressed in subjects with normal adrenal cortex tissue. Although endocan was expressed with a higher frequency in subjects with ACC and ACA, it was also expressed in subjects with normal adrenal cortex tissue. The percentage of cells expressed endocan in subjects with ACC was also significantly higher than in subjects with both ACA and normal adrenal cortex.

Melatonin counteracts polyethylene microplastics induced adreno-cortical damage in male albino rats.

There are various substances that can disrupt the homeostatic mechanisms of the body, defined as endocrine-disrupting chemicals (EDCs). The persistent nature of microplastics (MPs) is a cause for concern due to their ability to accumulate in food chains and widespread use, making their toxic effects particularly alarming. The potential of MPs for disrupting the endocrine system was observed in multiple tissues. Moreover, the adrenal gland is known to be extremely sensitive to EDCs, while with the effect of MPs on the adrenal gland has not previously been studied. This study aimed to highlight the potential polyethylene microplastics (PE-MPs) induced adreno-toxic effects rather than exploring the implicated mechanisms and concluding if melatonin (Mel) can afford protection against PE-MPs induced adreno-toxicity. To fulfill the goal, six groups of rats were used; control, Mel, PE-MPs (3.75 mg/kg), PE-MPs (15 mg/kg), PE-MPs (3.75 mg/kg) +Mel, and PE-MPs (15 mg/kg) +Mel. PE-MPs induced toxic changes in the adrenal cortex, which was evident by increased adrenal weight, histopathological examination, and ultrastructural changes detected by electron microscope. A reduction in serum cortisol and an increase in serum adrenocorticotropic hormone resulted from the adreno-toxic effects of PE-MPs. Mechanisms may include the reduction of steroidogenesis-related genes, as PE-MPs drastically reduce mRNA levels of StAR, Nr0b1, Cyp11A1, as well as Cyp11B1. Also, oxidative stress that results from PE-MPs is associated with higher rates of lipid peroxidation and decreased superoxide dismutase and glutathione. PE-MPs inflammatory effect was illustrated by elevated expression of IL-1ß and NF-kB, detected by immunohistochemical staining, in addition to increased expression of caspase-3 and mRNA of Bax, markers of proapoptotic activity. The impacts of PE-MPs were relatively dose-related, with the higher dose showing more significant toxicity than the lower one. Mel treatment was associated with a substantial amelioration of PE-MPs-induced toxic changes. Collectively, this study fills the knowledge gap about the MPs-induced adrenal cortex and elucidates various related toxic mechanisms. It also supports Mel's potential protective activity through antioxidant, anti-inflammatory, anti-apoptotic, and gene transcription regulatory effects.

Steroids-producing nodules: a two-layered adrenocortical nodular structure as a precursor lesion of cortisol-producing adenoma.

BACKGROUND: The human adrenal cortex consists of three functionally and structurally distinct layers; zona glomerulosa, zona fasciculata (zF), and zona reticularis (zR), and produces adrenal steroid hormones in a layer-specific manner; aldosterone, cortisol, and adrenal androgens, respectively. Cortisol-producing adenomas (CPAs) occur mostly as a result of somatic mutations associated with the protein kinase A pathway. However, how CPAs develop after adrenocortical cells acquire genetic mutations, remains poorly understood. METHODS: We conducted integrated approaches combining the detailed histopathologic studies with genetic, RNA-sequencing, and spatially resolved transcriptome (SRT) analyses for the adrenal cortices adjacent to human adrenocortical tumours. FINDINGS: Histopathological analysis revealed an adrenocortical nodular structure that exhibits the two-layered zF- and zR-like structure. The nodular structures harbour GNAS somatic mutations, known as a driver mutation of CPAs, and confer cell proliferative and autonomous steroidogenic capacities, which we termed steroids-producing nodules (SPNs). RNA-sequencing coupled with SRT analysis suggests that the expansion of the zF-like structure contributes to the formation of CPAs, whereas the zR-like structure is characterised by a macrophage-mediated immune response. INTERPRETATION: We postulate that CPAs arise from a precursor lesion, SPNs, where two distinct cell populations might contribute differently to adrenocortical tumorigenesis. Our data also provide clues to the molecular mechanisms underlying the layered structures of human adrenocortical tissues. FUNDING: KAKENHI, The Uehara Memorial Foundation, Daiwa Securities Health Foundation, Kaibara Morikazu Medical Science Promotion Foundation, Secom Science and Technology Foundation, ONO Medical Research Foundation, and Japan Foundation for Applied Enzymology.

Molecular tools for diagnosing diseases of the adrenal cortex.

PURPOSE OF REVIEW: The adrenal glands produce some of the most essential for life hormones, including cortisol and other steroids, and catecholamines. The former is produced from the adrenal cortex, whereas the latter is from the medulla. The two parts are anatomically and functionally distinct and it would be impossible in the context of one short article to cover all molecular updates on both the cortex and the medulla. Thus, in this review, we focus on the molecular tools available for diagnosing adrenocortical diseases, such as adrenal insufficiency, Cushing and Conn syndromes, and their potential for advancing medical care and clinical outcome. RECENT FINDINGS: The advent of next generation sequencing opened doors for finding genetic diseases and signaling pathways involved in adrenocortical diseases. In addition, the combination of molecular data and clinicopathologic assessment might be the best approach for an early and precise diagnosis contributing to therapeutic decisions and improvement of patient outcomes. SUMMARY: Diagnosing adrenocortical diseases can be challenging; however, the progress of molecular tools for adrenocortical disease diagnosis has greatly contributed to early detection and to meliorate patient outcomes.

[Morphological predictors of the efficacy of mitotane therapy in adrenocortical cancer].

BACKGROUND: Adrenocortical cancer (ACC) is an orphan malignant tumor of the adrenal cortex with a predominantly poor prognosis and an aggressive clinical course. Nowadays, mitotane is a non-alternative drug in the treatment of ACC. The search for prognostic parameters that determine the sensitivity of ACC to ongoing treatment is currently an urgent task. Expression levels of the large subunit of ribonucleotide reductase M1 (RRM1), cytochrome P450 2W1 (CYP2W1), and sterol- O-acyltransferase-1 (SOAT1) are considered as potential predictors of response to mitotane therapy. AIM: To assess the immunohistochemical expression of RRM1, CYP2W1 and SOAT1 in ACC as markers of clinical outcomes and response to the therapy with mitotane. MATERIALS AND METHODS: The study included 62 patients older than 17 years of age with a diagnosis of ACC confirmed histologically and immunohistochemically. Mitotane therapy was initiated in 29 patients in the postoperative period, 33 patients were under dynamic observation without concomitant drug treatment. Antibodies to RRM1, CYP2W1, SOAT1 were used diluted in accordance with recommendations of firms-manufacturers for immunohistochemical detection. RESULTS: In the group of patients with low and moderate RRM1, CYP2W1 and SOAT1 immunoreactivity in the tumor and no antitumor therapy, a better DFS was noted (p=0.037, p=0.020 and p=0.001, respectively) compared to the group of patients receiving mitotane therapy at this level of marker expression. With high immunoreactivity of the markers, no statistically significant differences in DFS were found. CONCLUSION: Consistent with the findings in our study, low expression of RRM1, CYP2W1 and SOAT1 was associated with worse DFS with antitumor therapy. The results of the work indicate the need to assess the levels of immunoreactivity of these markers in patients with ACC before starting treatment with mitotane in order to predict the efficiency of therapy.

Atypical hypoadrenocorticism with intact zona glomerulosa of the adrenal cortex after long-term observation: a case report of a dog.

An 8-year-old intact male pointer presented with lethargy and hypoalbuminemia. On abdominal ultrasonography, both adrenal glands were reduced in thickness. Based on the ACTH stimulation test results and the absence of electrolyte abnormalities, the dog was diagnosed with atypical hypoadrenocorticism. After treatment with low-dose prednisolone, his general condition improved, and blood tests normalized. The dog died 818 days later, and a complete autopsy was performed. Histologically, the architecture of the zonae fasciculata and reticularis was disrupted in both adrenal glands; however, the zona glomerulosa remained relatively normal. In summary, in this study, we detailed the pathological presentation of atypical hypoadrenocorticism without electrolyte abnormalities.

Histopathologic Features of Adrenal Cortical Carcinoma.

Adrenal cortical carcinoma (ACC) is a rare and aggressive malignancy that poses challenging issues regarding the diagnostic workup. Indeed, no presurgical technique or clinical parameters can reliably distinguish between adrenal cortical adenomas, which are more frequent and have a favorable outcome, and ACC, and the final diagnosis largely relies on histopathologic analysis of the surgical specimen. However, even the pathologic assessment of malignancy in an adrenal cortical lesion is not straightforward and requires a combined evaluation of multiple histopathologic features. Starting from the Weiss score, which was developed in 1984, several histopathologic scoring systems have been designed to tackle the difficulties of ACC diagnosis. Dealing with specific histopathologic variants (eg, Liss-Weiss-Bisceglia scoring system for oncocytic ACC) or patient characteristics (eg, Wieneke index in the pediatric setting), these scores remarkably improved the diagnostic workup of ACC and its subtypes. Nevertheless, cases with misleading features or discordant correlations between pathologic findings and clinical behavior still occur. Owing to multicentric collaborative studies integrating morphologic features with ancillary immunohistochemical markers and molecular analysis, ACC has eventually emerged as a multifaceted, heterogenous malignancy, and, while innovative and promising approaches are currently being tested, the future clinical management of patients with ACC will mainly rely on personalized medicine and target-therapy protocols. At the dawn of the new Fifth World Health Organization classification of endocrine tumors, this review will tackle ACC from the pathologist's perspective, thus focusing on the main available diagnostic, prognostic, and predictive tissue-tethered features and biomarkers and providing relevant clinical and molecular correlates.

[Benign and malignant neoplasms of the adrenal glands from the perspective of pathology]. / Benigne und maligne Neoplasien der Nebenniere aus der Sicht der Pathologie.

In the case of neoplasms of the adrenal glands that are radiologically and clinically unclear, the indications for surgical resection as well as the subsequent clarification of the entity and dignity on the surgical specimen are difficult. The diagnostics of adrenal neoplasms, in particular the clear distinction between an adenoma and a carcinoma are often tricky from the point of view of a pathologist. In the following, not only the problems of classification and the possibilities of diagnostics in pathology but also an overview of the most important differential diagnoses of other benign and malignant tumors of the adrenal cortex and medulla are presented.

Adrenal cortex ectopic tissue as an incidental finding in pediatric inguinal canal surgery: a case series.

The presence of ectopic adrenal remnants in the inguinal canal is an infrequent finding in pediatric patients. We performed a retrospective review of all pediatric patients diagnosed with ectopic adrenal tissue as an incidental finding during surgery of the inguinal canal at our center between 2000 and 2021. Six patients were included. The mean age was 3.83 ± 2.91 years. 3 (50%) were Arab and 3 (50%) were Caucasian. All patients were male. Five of the patients (83.3%) underwent surgery for testicular maldescent and one patient (16.6%) underwent surgery for a left hydrocele. 4 patients were operated on the right side (66%) and 2 on the left side (33%). Histologically, the presence of ectopic adrenal tissue was confirmed in all patients. All patients are healthy, discharged and under ambulatory follow-up. The existing literature suggests that ectopic adrenal remnants do not appear to have clinical or prognostic implications.

A Comprehensive Investigation of Steroidogenic Signaling in Classical and New Experimental Cell Models of Adrenocortical Carcinoma.

Adrenocortical carcinoma is a heterogeneous and aggressive cancer that originates from steroidogenic cells within the adrenal cortex. In this study, we have assessed for the preclinical gold standard NCI-H295 in direct comparison with the more recently established MUC-1 and a here newly reported ACC cell line (TVBF-7) the mutational status of important driver genes (TP53, MEN1, PRKAR1A, CTNNB1, APC, ZNRF-3, IGF-2, EGFR, RB1, BRCA1, BRCA2, RET, GNAS and PTEN), Wnt-signaling specificities (CTNNB1 mutation vs. APC mutation vs. wildtype), steroidogenic-(CYP11A1, CYP17A1, HSD3B2, HSD17B4, CYP21A2, CYP11B1, CYP11B2, MC2R, AT1R) and nuclear-receptor-signaling (AR, ER, GCR), varying electrophysiological potentials as well as highly individual hormone secretion profiles (Cortisol, Aldosterone, DHEA, DHEAS, Testosterone, 17-OH Progesterone, among others) which were investigated under basal and stimulated conditions (ACTH, AngII, FSK). Our findings reveal important genetic and pathophysiological characteristics for these three cell lines and reveal the importance of such cell-line panels reflecting differential endocrine functionalities to thereby better reflect clinically well-known ACC patient heterogeneities in preclinical studies.

Multiplatform computational analysis of mast cells in adrenocortical carcinoma tumor microenvironment.

BACKGROUND: Immunotherapeutic response failure of adrenocortical carcinomas highlights a need for novel strategies targeting immune cell populations in the tumor microenvironment to overcome tumor resistance and enhance therapeutic response. A recent study explored a new link between tumor mast cell infiltration and improved outcomes in patients with adrenocortical carcinomas. We further dissect the role of mast cells in the tumor microenvironment of adrenocortical carcinomas by examining the tumor mast cell expression signatures and mast cell activity within the tumor microenvironment to provide additional insight into potential novel immunotherapeutic targets. METHODS: Using the CIBERSORTx computational immunogenomic deconvolution algorithm to analyze adrenocortical carcinoma tumor gene messenger RNA expression data (The Cancer Genome Atlas, N = 79), we estimated the abundance of tumor immune infiltrating mast cells and assessed prognostic potential of mast cell signaling genes as pro or antitumor signatures, as well as examined the impact on overall and disease-free survival. RESULTS: We stratified mast cell signaling genes with survival prognostic values (overall survival, disease-free survival, P < .05) into antitumor (ALOX5, CCL2, CCL5, CXCL10, HDC, IL16, TNF, TPSAB1, VEGFD) and protumor (CXCL1, CXCL3, CXCL8, IL4, IL13, PTGS3, TNSF4, VEGFD) groups. Antitumor mast cell signature, as the predominant phenotype, was associated with improved overall and disease-free survival. CONCLUSION: The deconvolution analysis of The Cancer Genome Atlas data identified mast cell infiltration in the adrenocortical carcinoma microenvironment as predominantly associated with antitumor activity. Future studies stemming from our findings may help define the role of mast cells in the tumor microenvironment and the impact on patient survival in patients with adrenocortical carcinomas. Modulation of tumor mast cell infiltration may serve as a potential target for novel synergistic immunotherapies for the treatment and improved survival of patients with adrenocortical carcinomas.

Colocalization of Wnt/ß-Catenin and ACTH Signaling Pathways and Paracrine Regulation in Aldosterone-producing Adenoma.

CONTEXT: Aldosterone-producing adenomas (APAs) are a common cause of primary aldosteronism (PA). Despite the discovery of somatic mutations in APA and the characterization of multiple factors regulating adrenal differentiation and function, the sequence of events leading to APA formation remains to be determined. OBJECTIVE: We investigated the role of Wnt/ß-catenin and adrenocorticotropin signaling, as well as elements of paracrine regulation of aldosterone biosynthesis in adrenals with APA and their relationship to intratumoral heterogeneity and mutational status. METHODS: We analyzed the expression of aldosterone-synthase (CYP11B2), CYP17A1, ß-catenin, melanocortin type 2 receptor (MC2R), phosphorlyated cAMP response element-binding protein (pCREB), tryptase, S100, CD34 by multiplex immunofluorescence, and immunohistochemistry-guided reverse transcription-quantitative polymerase chain reaction. Eleven adrenals with APA and 1 with micronodular hyperplasia from patients with PA were analyzed. Main outcome measures included localization of CYP11B2, CYP17A1, ß-catenin, MC2R, pCREB, tryptase, S100, CD34 in APA and aldosterone-producing cell clusters (APCCs). RESULTS: Immunofluorescence revealed abundant mast cells and a dense vascular network in APA, independent of mutational status. Within APA, mast cells were localized in areas expressing CYP11B2 and were rarely colocalized with nerve fibers, suggesting that their degranulation is not controlled by innervation. In these same areas, ß-catenin was activated, suggesting a zona glomerulosa cell identity. In heterogeneous APA with KCNJ5 mutations, MC2R and vascular endothelial growth factor A expression was higher in areas expressing CYP11B2. A similar pattern was observed in APCC, with high expression of CYP11B2, activated ß-catenin, and numerous mast cells. CONCLUSION: Our results suggest that aldosterone-producing structures in adrenals with APA share common molecular characteristics and cellular environment, despite different mutation status, suggesting common developmental mechanisms.

Computed tomography (CT) scan identified necrosis, but is it a reliable single parameter for discerning between malignant and benign adrenocortical tumors?

BACKGROUND: Adrenocortical carcinoma is a rare malignant tumor with a poor prognosis. Discernment of adrenocortical carcinoma in an adrenal mass through imaging studies is paramount for early surgical treatment. Recently, necrosis has been proposed as a single morphological parameter for adrenocortical carcinoma diagnosis. The aim of this study was to analyze the measures of diagnostic efficiency of necrosis and the different computed tomography-scan features related to adrenocortical carcinoma diagnosis. METHODS: We conducted a case-control study of patients surgically treated for an adrenal mass with histopathological report consistent with adrenocortical carcinoma (cases) and adrenocortical adenoma (control patients) between 1987 and 2019. Radiological features on computed tomography scan were collected. Bivariate and multivariate statistical analyses were performed for the different imaging features. The measures of diagnostic efficiency for each feature were calculated. Concordance analysis between image-detected and histopathological-identified necrosis was performed. RESULTS: Eighteen adrenocortical carcinoma and 41 adrenocortical adenomas were included. Differences between adrenocortical carcinoma and adrenocortical adenoma were found regarding heterogeneity (odds ratio 4.53, 95% confidence interval 2.3-8.9; P < .0001), tumor size ≥4 cm (odds ratio 3.5, 95% confidence interval 2.05-6.14; P < .0001), and attenuation index ≥10 Hounsfield units (odds ratio 1.9, 95% confidence interval 1.3-2.6; P = .001). Necrosis was the most important imaging feature significantly associated with adrenocortical carcinoma (odds ratio 35, 95% confidence interval 5.1-241.6; P < .0001), present in all adrenocortical carcinoma cases. After measures of diagnostic efficiency calculation, necrosis had the highest diagnostic accuracy (98%). Cohen's kappa for concordance between image-detected and histopathological-identified necrosis was 90.4% (P < .0001). CONCLUSION: Computed tomography scan-detected necrosis is a reliable radiological feature to discern adrenocortical carcinoma from adrenocortical adenomas.

Cellular Senescence in Adrenocortical Biology and Its Disorders.

Cellular senescence is considered a physiological process along with aging and has recently been reported to be involved in the pathogenesis of many age-related disorders. Cellular senescence was first found in human fibroblasts and gradually explored in many other organs, including endocrine organs. The adrenal cortex is essential for the maintenance of blood volume, carbohydrate metabolism, reaction to stress and the development of sexual characteristics. Recently, the adrenal cortex was reported to harbor some obvious age-dependent features. For instance, the circulating levels of aldosterone and adrenal androgen gradually descend, whereas those of cortisol increase with aging. The detailed mechanisms have remained unknown, but cellular senescence was considered to play an essential role in age-related changes of the adrenal cortex. Recent studies have demonstrated that the senescent phenotype of zona glomerulosa (ZG) acts in association with reduced aldosterone production in both physiological and pathological aldosterone-producing cells, whereas senescent cortical-producing cells seemed not to have a suppressed cortisol-producing ability. In addition, accumulated lipofuscin formation, telomere shortening and cellular atrophy in zona reticularis cells during aging may account for the age-dependent decline in adrenal androgen levels. In adrenocortical disorders, including both aldosterone-producing adenoma (APA) and cortisol-producing adenoma (CPA), different cellular subtypes of tumor cells presented divergent senescent phenotypes, whereby compact cells in both APA and CPA harbored more senescent phenotypes than clear cells. Autonomous cortisol production from CPA reinforced a local cellular senescence that was more severe than that in APA. Adrenocortical carcinoma (ACC) was also reported to harbor oncogene-induced senescence, which compensatorily follows carcinogenesis and tumor progress. Adrenocortical steroids can induce not only a local senescence but also a periphery senescence in many other tissues. Therefore, herein, we systemically review the recent advances related to cellular senescence in adrenocortical biology and its associated disorders.

Adrenocortical Tumors in Children With Constitutive Chromosome 11p15 Paternal Uniparental Disomy: Implications for Diagnosis and Treatment.

Pediatric adrenocortical tumors (ACTs) are rare and heterogeneous. Approximately 50% of children with ACT carry a germline TP53 variant; however, the genetic underpinning of remaining cases has not been elucidated. In patients having germline TP53 variants, loss of maternal chromosome 11 and duplication of the paternal copy [paternal uniparental disomy, (UPD)] occurs early in tumorigenesis and explains the overexpression of IGF2, the hallmark of pediatric ACT. Beckwith-Wiedemann syndrome (BWS) is also associated with overexpression of IGF2 due to disruption of the 11p15 loci, including segmental UPD. Here, we report six children with ACT with wild type TP53 and germline paternal 11p15 UPD. Median age of five girls and one boy was 3.2 years (range 0.5-11 years). Two patients met the criteria for BWS before diagnosis of ACT. However, ACT was the first and only manifestation of paternal 11p15 UPD in four children. Tumor weight ranged from 21.5 g to 550 g. Despite poor prognostic features at presentation, such as pulmonary metastasis, bilateral adrenal involvement, and large tumors, all patients are alive 8-21 years after cancer diagnosis. Our observations suggest that children with ACT and wild type TP53, irrespective of their age, should be screened for germline abnormalities in chromosome 11p15.

Latent Adrenal Insufficiency: From Concept to Diagnosis.

Primary adrenal insufficiency (PAI) is a rare disease and potentially fatal if unrecognized. It is characterized by destruction of the adrenal cortex, most frequently of autoimmune origin, resulting in glucocorticoid, mineralocorticoid, and adrenal androgen deficiencies. Initial signs and symptoms can be nonspecific, contributing to late diagnosis. Loss of zona glomerulosa function may precede zona fasciculata and reticularis deficiencies. Patients present with hallmark manifestations including fatigue, weight loss, abdominal pain, melanoderma, hypotension, salt craving, hyponatremia, hyperkalemia, or acute adrenal crisis. Diagnosis is established by unequivocally low morning serum cortisol/aldosterone and elevated ACTH and renin concentrations. A standard dose (250 µg) Cosyntropin stimulation test may be needed to confirm adrenal insufficiency (AI) in partial deficiencies. Glucocorticoid and mineralocorticoid substitution is the hallmark of treatment, alongside patient education regarding dose adjustments in periods of stress and prevention of acute adrenal crisis. Recent studies identified partial residual adrenocortical function in patients with AI and rare cases have recuperated normal hormonal function. Modulating therapies using rituximab or ACTH injections are in early stages of investigation hoping it could maintain glucocorticoid residual function and delay complete destruction of adrenal cortex.

Concurrence of overt Cushing's syndrome and primary aldosteronism accompanied by aldosterone-producing cell cluster in adjacent adrenal cortex: case report.

BACKGROUND: Various adrenal disorders including primary aldosteronism and Cushing's syndrome lead to the cause of hypertension. Although primary aldosteronism is sometimes complicated with preclinical Cushing's syndrome, concurrence of overt Cushing's syndrome and primary aldosteronism is very rare. In addition, it has been drawing attention recently that primary aldosteronism is brought about by the presence of aldosterone-producing cell cluster in adjacent adrenal cortex rather than the presence of aldosterone-producing adenoma. CASE PRESENTATION: A 67-year-old Japanese female was referred to our institution due to moon face and central obesity. Based on various clinical findings and data, we diagnosed this subject as overt Cushing's syndrome and primary aldosteronism. Furthermore, in immunostaining for cytochrome P450 (CYP) 11B1, a cortisol-producing enzyme, diffuse staining was observed in tumorous lesion. Also, in immunostaining for CYP11B2, an aldosterone-producing enzyme, CYP11B2 expression was not observed in tumorous lesion, but strong CYP11B2 expression was observed in adjacent adrenal cortex, indicating the presence of aldosterone-producing cell cluster. CONCLUSIONS: We should bear in mind the possibility that concurrence of overt Cushing's syndrome and primary aldosteronism is accompanied by aldosterone-producing cell cluster in adjacent adrenal cortex.

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.

Steroidogenic cell microenvironment and adrenal function in physiological and pathophysiological conditions.

The human adrenal cortex is a complex organ which is composed of various cell types including not only steroidogenic cells but also mesenchymal cells, immunocompetent cells and neurons. Intermingling of these diverse cell populations favors cell-to-cell communication processes involving local release of numerous bioactive signals such as biogenic amines, cytokines and neuropeptides. The resulting paracrine interactions play an important role in the regulation of adrenocortical cell functions both in physiological and pathophysiological conditions. Especially, recent evidence indicates that adrenocortical cell microenvironment is involved in the pathogenesis of adrenal disorders associated with corticosteroid excess. The paracrine factors involved in these intraadrenal regulatory mechanisms may thus represent valuable targets for future pharmacological treatments of adrenal diseases.