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Background: It is challenging for clinicians to distinguish adrenocortical carcinoma (ACC) from benign adrenocortical adenomas (ACA) in their early stages. This study explored the value of serum steroid profiling as a complementary biomarker for malignancy diagnosis of ACC other than diameter and explored the influence of sex and functional status., Methods: In this retrospective study, a matched cohort of patients diagnosed with either ACC or ACA based on histopathology was meticulously paired in a 1:1 ratio according to sex, age, and functional status. Eight serum steroids including 11-deoxycortisol, 11-deoxycorticosterone, progesterone, androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), 17-hydroxyprogesterone, and estradiol, were quantified by liquid chromatography tandem mass spectrometry. We conducted a comparative analysis of the clinical characteristics and serum steroid profiles of patients with ACC and ACA, with further subgroup analysis., Results: The study included 31 patients with ACC and 31 matched patients with ACA. Patients with ACC exhibited significantly larger tumor diameters, lower body mass index (BMI), and higher levels of 11-deoxycortisol, progesterone, and androstenedione than those with ACA. 11-deoxycortisol was the only valuable index for discriminating ACC from ACA, regardless of functional status and sex. Progesterone, DHEA, and DHEAS levels were higher in the functional ACC group than in the non-functional ACC group. Female ACC patients, especially in postmenopausal female exhibited higher levels of androstenedione than male patients. The area under the curve of tumor diameter, 11-deoxycortisol, and BMI was 0.947 (95% CI 0.889-1.000), with a sensitivity of 96.8% and specificity of 90.3%., Conclusion: Serum steroid profiling serves as a helpful discriminative marker for ACC and ACA, with 11-deoxycortisol being the most valuable marker. For other steroid hormones, consideration of sex differences and functional status is crucial., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Weng, Tang, Zhang, Lin, Guo, Liang, Wang, Zhou, Yan, Lin and Zhang.)

Context: The search for somatic mutations in adrenals resected from patients with primary aldosteronism (PA) is performed by Sanger sequencing, often implemented with immunohistochemistry (IHC)-guidance focused on aldosterone-producing (CYP11B2-positive) areas., Objective: To investigate the impact of double IHC for CYP11B1 and CYP11B2 on Sanger and next-generation sequencing (NGS)., Methods: We investigated 127 consecutive adrenal aldosterone-producing adenomas from consenting surgically cured PA patients using double IHC for CYP11B1 and CYP11B2, by Sanger sequencing and NGS., Results: Double IHC for CYP11B2 and CYP11B1 revealed 3 distinct patterns: CYP11B2-positive adenoma (pattern 1), mixed CYP11B1/CYP11B2-positive adenoma (pattern 2), and adrenals with multiple small CYP11B2-positive nodules (pattern 3). Sanger sequencing allowed detection of KCNJ5 mutations in 44% of the adrenals; NGS revealed such mutations in 10% of those negative at Sanger and additional mutations in 61% of the cases. Importantly the rate of KCNJ5 mutations differed across patterns: 17.8% in pattern 1, 71.4% in pattern 2, and 10.7% in pattern 3 (χ2 = 22.492, P < .001)., Conclusion: NGS allowed detection of mutations in many adrenals that tested negative at Sanger sequencing. Moreover, the different distribution of KCNJ5 mutations across IHC patterns indicates that IHC-guided sequencing protocols selecting CYP11B2-positive areas could furnish results that might not be representative of the entire mutational status of the excised adrenal, which is important at a time when KCNJ5 mutations are suggested to drive management of patients with aldosterone-producing adenomas., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Objective: To develop and validate a nomogram combining radiomics and pathology features to distinguish between aldosterone-producing adenomas (APAs) and nonfunctional adrenal adenomas (NF-AAs)., Methods: Consecutive patients diagnosed with adrenal adenomas via computed tomography (CT) or pathologic analysis between January 2011 and November 2022 were eligible for inclusion in this retrospective study. CT images and hematoxylin & eosin-stained slides were used for annotation and feature extraction. The selected radiomics and pathology features were used to develop a risk model using various machine learning models, and the area under the receiver operating characteristic curve (AUC) was determined to evaluate diagnostic performance. The predicted results from radiomics and pathology features were combined and visualized using a nomogram., Results: A total of 211 patients (APAs, n = 59; NF-AAs, n = 152) were included in this study, with patients randomly divided into either the training set or the testing set at a ratio of 8:2. The ExtraTrees model yielded a sensitivity of 0.818, a specificity of 0.733, and an accuracy of 0.756 (AUC = 0.817; 95% confidence interval [CI]: 0.675-0.958) in the radiomics testing set and a sensitivity of 0.999, a specificity of 0.842, and an accuracy of 0.867 (AUC = 0.905, 95% CI: 0.792-1.000) in the pathology testing set. A nomogram combining radiomics and pathology features demonstrated a strong performance (AUC = 0.912; 95% CI: 0.807-1.000)., Conclusion: A nomogram combining radiomics and pathology features demonstrated strong predictive accuracy and discrimination capability. This model may help clinicians to distinguish between APAs and NF-AAs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Adrenal tumors, such as adrenocortical carcinoma (ACC), adrenocortical adenoma (ACA), and pheochromocytoma (PCC) are complex diseases with unclear causes and treatments. Mitochondria and mitochondrial-derived peptides (MDPs) are crucial for cancer cell survival. The primary aim of this study was to analyze samples from different adrenal diseases, adrenocortical carcinoma, adrenocortical adenoma, and pheochromocytoma, and compare them with normal adrenal tissue to determine whether the expression levels of the mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) gene and protein vary between different types of adrenal tumors compared to healthy controls using qPCR, ELISA, and IHC methods. Results showed decreased MOTS-c mRNA expression in all adrenal tumors compared to controls, while serum MOTS-c protein levels increased in ACA and PCC but not in ACC. The local distribution of MOTS-c protein in adrenal tissue was reduced in all tumors. Notably, MOTS-c protein expression declined with ACC progression (stages III and IV) but was unrelated to patient age or sex. Tumor size and testosterone levels positively correlated with MOTS-c mRNA but negatively with serum MOTS-c protein. Additionally, serum MOTS-c protein correlated positively with glucose, total cholesterol, HDL, LDL, and SHGB levels. These findings suggest disrupted expression of MOTS-c in the spectrum of adrenal diseases, which might be caused by mechanisms involving increased mitochondrial dysfunction and structural changes in the tissue associated with disease progression. This study provides a detailed examination of MOTS-c mRNA and protein in adrenal tumors, indicating the potential role of MDPs in tumor biology and progression., Competing Interests: The authors declare no conflict of interest.

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.

Background: Many adrenal tumors are deemed radiologically indeterminate and surgically removed. Adrenal tissue, like parathyroid glands, exhibits near-infrared autofluorescence (NIRAF) properties. This study was designed to investigate the potential of NIRAF to differentiate benign versus malignant adrenal tumors., Methods: Patients undergoing adrenalectomy between October 2021 and May 2023 were prospectively studied. Adrenalectomy specimens were inspected with NIRAF imaging. Specimen autofluorescence (AF) characteristics were recorded. Comparisons were made between different tumor types and a logistic regression model was constructed to differentiate benign versus malignant tumors. A receiver operating characteristic curve was used to identify an optimal AF threshold differentiating benign versus malignant tumors., Results: A total of 108 adrenal specimens were examined: adrenocortical adenomas/other benign lesions (n = 72), pheochromocytomas (n = 18), adrenocortical neoplasms of uncertain behavior (n = 4), and malignant tumors (n = 14). A significant difference in normalized AF intensity was identified when comparing adrenocortical adenomas (3.08 times background) with pheochromocytomas (1.95, p = 0.001) and malignant tumors (1.11, p < 0.0001). The Area Under the Curve differentiating benign vs malignant tumors was 0.87, with an optimal normalized AF threshold at 1.93., Conclusions: Different adrenal pathologies exhibit diverse AF properties. These findings suggest a potential intraoperative utility of NIRAF in predicting benign versus malignant nature for radiologically indeterminate adrenal tumors., (© 2024. The Author(s).)

Background: Functioning adrenal adenoma during pregnancy is rare, and the diagnosis is challenging owing to unspecific symptoms and restricted investigations. The obstetric outcomes of patients who undergo surgery during pregnancy or who receive only medical treatment are poorly described., Objective: The aim was to investigate the associations between functioning adrenal adenomas and obstetric outcomes., Methods: A retrospective study was performed in a tertiary center over 20 years. The clinical characteristics, management and obstetric outcomes of the diagnosed pregnant women were reviewed., Results: A total of 12 women were diagnosed with functioning adrenal adenomas during pregnancy from January 2002 to September 2022. Eight women had cortisol-secreting adrenal adenomas, two had excessive catecholamine secretion, and two had primary aldosteronism. The initial symptoms of adrenal adenoma during pregnancy included hypertension or preeclampsia, gestational diabetes mellitus or prepregnancy diabetes mellitus, hypokalemia and ecchymosis. Four women underwent adrenalectomy during pregnancy, while 8 women received only medical therapy. Preterm birth occurred in all patients who received medicine, whereas 1 patient who underwent surgery experienced preterm birth. Among the 8 women in the medical treatment group, 3 had neonates who died., Conclusions: Once hypertension, hyperglycemia and hypokalemia occur during the 1st or 2nd trimester, pregnant women with adrenal adenomas should be evaluated via laboratory and imaging examinations. The maternal and fetal outcomes were unpredictable owing to the severity of adrenal adenoma, particularly in patients who received only medical treatment. Adrenalectomy should be recommended during pregnancy., (© 2024. The Author(s).)

Background: Somatic mutations have been observed to induce aldosterone-producing adenomas (APAs). These may be accelerated during pregnancy. Somatic PRKACA mutations are common in cortisol-producing adenomas (CPAs). However, their role in APAs, particularly aldosterone- and cortisol-producing adenomas (A/CPAs), is not well understood. This study aims to investigate the association between PRKACA mutations and the accelerated development of A/CPAs during pregnancy., Case Presentation: A patient with primary aldosteronism (PA) associated with severe Cushing's syndrome (CS) underwent surgical resection of an adrenal tumor one year after delivery. Pathologic examination revealed an adrenocortical adenoma characterized primarily by zona glomerulosa hyperplasia. Somatic mutation analysis revealed the presence of the somatic PRKACA mutation, which was validated as a deleterious mutation by various computational databases. Immunohistochemical results showed positive staining for cytochrome P450 family 11 subfamily B member 1 (CYP11B1), cytochrome P450 family 11 subfamily B member 2 (CYP11B2), and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). Our study included a review of 20 previously documented cases of aldosterone- and cortisol-producing adenomas (A/CPAs), two of which were concurrently positive for both CYP11B1 and CYP11B2, consistent with our findings., Conclusion: Somatic mutations in PRKACA may correlate with the upregulation of LHCGR, which synergistically drives the accelerated growth of co-secretion tumors during pregnancy, thereby exacerbating disease progression., (© 2024. The Author(s).)

Objective: The aim of this study is to assess whether clinical and imaging characteristics are associated with the hormonal subtype, growth, and adrenalectomy for incidental adrenal cortical adenomas (ACAs)., Design: This is a single-center cohort study., Methods: Consecutive adult patients with incidental ACA were diagnosed between 2000 and 2016., Results: Of the 1516 patients with incidental ACA (median age 59 years, 62% women), 699 (46%) had nonfunctioning adenomas (NFAs), 482 (31%) had mild autonomous cortisol secretion (MACS), 62 (4%) had primary aldosteronism (PA), 39 (3%) had Cushing syndrome, 18 (1%) had PA and MACS, and 226 (15%) had incomplete work-up. Age, sex, tumor size, and tumor laterality, but not unenhanced computed tomography Hounsfield units (HU), were associated with hormonal subtypes. In a multivariable analysis, ≥1 cm growth was associated with younger age (odds ratio [OR] = 0.8 per 5-year increase, P = .0047) and longer imaging follow-up (OR = 1.2 per year, P < .0001). Adrenalectomy was performed in 355 (23%) patients, including 38% of MACS and 15% of NFA. Adrenalectomy for NFA and MACS was more common in younger patients (OR = 0.79 per 5-year increase, P = .002), larger initial tumor size (OR = 2.3 per 1 cm increase, P < .0001), ≥1 cm growth (OR = 15.3, P < .0001), and higher postdexamethasone cortisol (OR = 6.6 for >5 vs <1.8 μg/dL, P = .002)., Conclusions: Age, sex, tumor size, and laterality were associated with ACA hormonal subtype and can guide diagnosis and management. Tumor growth was more common with younger age and longer follow-up. Unenhanced HU did not predict hormonal subtype or growth. Adrenalectomy for MACS and NFA was mainly performed in younger patients with larger tumor size, growth, and elevated postdexamethasone cortisol., Competing Interests: Conflict of interest: I.B. reports consulting or advisory board participation with Corcept Therapeutics, HRA Pharma, Sparrow Pharmaceuticals, Recordati Rare Diseases, Neurocrine Biosciences, Diurnal, Sparrow, Novo Nordisk, AstraZeneca, Xeris, and Adrenas outside the submitted work and reports funding from Recordati and HRA Pharma outside this work. I.B. is on the editorial board of EJE. She was not involved in the review or editorial process for this paper, on which she is listed as coauthor. O.H. reports advisory board participation with Corcept Therapeutics, Recordati Rare Diseases, Amryt Pharma, Xeris, Lantheus, and Neurocrine Biosciences outside the submitted work. D.L. is currently an employee of BridgeBio Pharma, which is unrelated to the submitted work., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Currently, there is a scarcity of cases and diagnostic data regarding ectopic adrenocortical adenomas, particularly in relation to their impact on gonadal function and localization diagnostic techniques. We report a typical case of ectopic adrenocortical adenomas and the data of treatment follow-up, and review the literature of 31 available cases of ectopic adrenocortical adenomas., Case Presentation: A 27-year-old Chinese female patient was admitted to our hospital for hypertension, hyperglycaemia and primary amenorrhea. The patient was functionally diagnosed with ACTH-independent CS and hypogonadotropic hypogonadism. Radiological evaluations, including Computed Tomography (CT) and functional imaging, identified a mass at the left renal hilum. Histological assessments post-surgical excision confirmed the mass to be an ectopic adrenocortical adenoma. A subsequent 3-month follow-up showed no signs of disease recurrence, a swift recovery of the cortisol axis was observed, with a partial recuperation of the gonadal axis., Review: Our literature review shows that the most common ectopic areas of cortisol adenomas are renal hilum and hepatic region. The most positive biomarker is Melan A, and only a few cases have been diagnosed with functional localization., Conclusion: Ectopic adrenocortical adenomas may be asymptomatic in the early stage and can impact gonadal function. Physicians who treat hypogonadism must be aware of the need to test cortisol levels and perform functional localization in patients with lumps present., (© 2024. The Author(s).)

Adrenocortical tumours are rare in children and account for only 0.3%-0.4% of all neoplasms in childhood. They present with variable signs and symptoms, depending on the type of hormonal hypersecretion. The majority of the adrenocortical tumours in children are functional (90%) and malignant (88%). Here, we describe a functional plurihormonal oncocytic adrenal cortical adenoma in a young girl, that mimicked a malignant adrenal lesion, clinically as well as on imaging and biochemical features. This report bears the objective of being aware of the atypical biochemical as well as imaging characteristics of oncocytic adrenal tumours., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Current diagnostic criteria of adrenocortical neoplasms are mostly based on morphology. The utility of immunohistochemistry (IHC) and histochemistry is limited., Materials and Methods: To evaluate the diagnostic and prognostic utility of clinicopathological features, morphology, ancillary biomarkers, and reticular histochemistry in adrenocortical neoplasms. We examined 28 adrenocortical carcinomas (ACCs) and 50 adrenocortical adenomas (ACAs) obtained from pathology archives. Clinical data were retrieved from medical records. Two pathologists independently assessed hematoxylin and eosin-stained slides, employing modified Weiss criteria for all tumors and Lin-Weiss-Bisceglia criteria for oncocytic variants. Immunohistochemical markers (Calretinin, alpha-inhibin, MelanA, SF-1, Ki-67, PHH3, IGF-2, β-catenin, P53, CYP11B1, CYP11B2, MLH1, MSH2, MSH6, PMS2, EPCAM) and Gomori's Silver histochemistry were applied. Statistical analysis utilized SPSS Statistics 26., Results: ACCs exhibited larger tumor sizes (P<0.001) and symptomatic presentations (P = 0.031) compared to ACAs. Parameters of modified Weiss criteria and angioinvasion demonstrated diagnostic value for ACCs. Six immunohistochemical antibodies((MelanA, Ki-67, IGF-2, β-catenin, P53 and CYP11B1) and reticulin framework alterations showed diagnostic value. Notably, Ki-67 and reticulin staining were most recommended. Evident reticulin staining was frequently present in ACCs (P<0.001). Ki-67 was significantly higher in ACCs (P<0.001). Twenty-one conventional and seven oncocytic entities showed different necrosis frequencies. Symptoms and Ki-67 index ≥ 30% were prognostic for ACCs, correlating with shorter survival., Conclusions: This study emphasizes the diagnostic value of reticulin framework alterations and a high Ki-67 index. Markers such as CYP11B1, IGF2, P53, β-catenin and MelanA also contribute to the diagnosis of ACCs. Symptoms and Ki-67 index ≥ 30% predict shorter survival. These findings encourges the use of ancillary markers such as reticulin histochemistry and Ki-67 in the workup of evaluations of adrenocortical neoplasms., (© 2024. The Author(s).)

Introduction: The fluctuations of the intracellular Ca 2+ concentration ([Ca 2+ ] i ) are key physiological signals for cell function under normal conditions and can undergo profound alterations in disease states, as high blood pressure due to endocrine disorders like primary aldosteronism (PA). However, when assessing such fluctuations several parameters in the Ca 2+ signal dynamics need to be considered, which renders their assessment challenging., Aim: Aim to develop an observer-independent custom-made pipeline to analyze Ca 2 + dynamics in terms of frequency and peak parameters, as amplitude, full width at half maximum (FWHM) and area under the curve (AUC)., Methods: We applied a custom-made methodology to aldosterone-producing adenoma (APA) and APA adjacent cells (AAC) and found this pipeline to be suitable for monitoring and processing a wide-range of [Ca 2+ ] i events in these cell types delivering reproducible results., Conclusion: The designed pipeline can provide a useful tool for [Ca 2+ ] i signal analysis that allows comparisons of Ca 2+ dynamics not only in PA, but in other cell phenotypes that are relevant for the regulation of blood pressure., (© 2024. The Author(s).)

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., Competing Interests: Declaration of interests The authors have declared that no conflict of interest exists., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Recent advances in omics techniques have allowed detailed genetic characterization of aldosterone-producing adenoma (APA). The pathogenesis of APA is characterized by tumorigenesis-associated aldosterone synthesis. The pathophysiological intricacies of APAs have not yet been elucidated at the level of individual cells. Therefore, a single-cell level analysis is speculated to be valuable in studying the differentiation process of APA., Methods: We conducted single-nucleus RNA sequencing of APAs with KCNJ5 mutation and nonfunctional adenomas obtained from 3 and 2 patients, respectively., Results: The single-nucleus RNA sequencing revealed the intratumoral heterogeneity of APA and identified cell populations consisting of a shared cluster of nonfunctional adenoma and APA. In addition, we extracted 2 cell fates in APA and obtained a cell population specialized in aldosterone synthesis. Genes related to ribosomes and neurodegenerative diseases were upregulated in 1 of these fates, whereas those related to the regulation of glycolysis were upregulated in the other fate. Furthermore, the total RNA reads in the nucleus were higher in hormonally activated clusters, indicating a marked activation of transcription per cell., Conclusions: The single-nucleus RNA sequencing revealed intratumoral heterogeneity of APA with KCNJ5 mutation. The observation of 2 cell fates in KCNJ5 -mutated APAs provides the postulation that a heterogeneous process of cellular differentiation was implicated in the pathophysiological mechanisms underlying APA tumors., Competing Interests: Disclosures None.

The measurement of steroid hormones in blood and urine, which reflects steroid biosynthesis and metabolism, has been recognized as a valuable tool for identifying and distinguishing steroidogenic disorders. The application of mass spectrometry enables the reliable and simultaneous analysis of large panels of steroids, ushering in a new era for diagnosing adrenal diseases. However, the interpretation of complex hormone results necessitates the expertise and experience of skilled clinicians. In this scenario, machine learning techniques are gaining worldwide attention within healthcare fields. The clinical values of combining mass spectrometry-based steroid profiles analysis with machine learning models, also known as steroid metabolomics, have been investigated for identifying and discriminating adrenal disorders such as adrenocortical carcinomas, adrenocortical adenomas, and congenital adrenal hyperplasia. This promising approach is expected to lead to enhanced clinical decision-making in the field of adrenal diseases. This review will focus on the clinical performances of steroid profiling, which is measured using mass spectrometry and analyzed by machine learning techniques, in the realm of decision-making for adrenal diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Aim: We present a case of adrenocortical adenoma originating from the adrenohepatic fusion (AHF) region, accompanied by advanced hepatosteatosis in the liver tissue, and discuss its distinction from hepatocellular carcinoma.  Case Experience: A 68-year-old male patient was admitted to the hospital following a fall from a height. He was referred to our hospital after an incidental discovery of a liver mass during an abdominal ultrasound examination. Subsequently, magnetic resonance imaging (MRI) imaging was conducted, followed by segmental liver resection with right adrenalectomy, and histological analysis of a biopsy from the lesion.  Results: Upon histologic examination, the case was determined to be an adrenocortical adenoma originating from the AHF.  Discussion: Adrenohepatic fusion (AHF) denotes the histological amalgamation of cells from the right adrenal cortex and right hepatic parenchyma. Only a limited number of cases of neoplasia originating from this region have been documented. These rare instances often present a diagnostic challenge, with preoperative imaging frequently misidentifying them as primary malignancies of either hepatic or adrenal origin, potentially leading to unnecessary extensive resections. The integration of immunohistochemical staining alongside clinical and radiological data proves helpful for accurately diagnosing this condition.  Conclusion: Awareness among clinicians, radiologists, and pathologists regarding the tumors that may arise from this region can mitigate the risk of performing extensive resections unnecessarily.

Purpose: Distinguishing stage 1-2 adrenocortical carcinoma (ACC) and large, lipid poor adrenal adenoma (LPAA) via imaging is challenging due to overlapping imaging characteristics. This study investigated the ability of deep learning to distinguish ACC and LPAA on single time-point CT images., Methods: Retrospective cohort study from 1994 to 2022. Imaging studies of patients with adrenal masses who had available adequate CT studies and histology as the reference standard by method of adrenal biopsy and/or adrenalectomy were included as well as four patients with LPAA determined by stability or regression on follow-up imaging. Forty-eight (48) subjects with pathology-proven, stage 1-2 ACC and 43 subjects with adrenal adenoma >3 cm in size demonstrating a mean non-contrast CT attenuation > 20 Hounsfield Units centrally were included. We used annotated single time-point contrast-enhanced CT images of these adrenal masses as input to a 3D Densenet121 model for classifying as ACC or LPAA with five-fold cross-validation. For each fold, two checkpoints were reported, highest accuracy with highest sensitivity (accuracy focused) and highest sensitivity with the highest accuracy (sensitivity focused)., Results: We trained a deep learning model (3D Densenet121) to predict ACC versus LPAA. The sensitivity-focused model achieved mean accuracy: 87.2% and mean sensitivity: 100%. The accuracy-focused model achieved mean accuracy: 91% and mean sensitivity: 96%., Conclusion: Deep learning demonstrates promising results distinguishing between ACC and large LPAA using single time-point CT images. Before being widely adopted in clinical practice, multicentric and external validation are needed., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Adrenocortical cancer (ACC) is a rare malignant tumor that originates in the adrenal cortex. Despite extensive molecular-genetic, pathomorphological, and clinical research, assessing the malignant potential of adrenal neoplasms in clinical practice remains a daunting task in histological diagnosis. Although the Weiss score is the most prevalent method for diagnosing ACC, its limitations necessitate additional algorithms for specific histological variants. Unequal diagnostic value, subjectivity in evaluation, and interpretation challenges contribute to a gray zone where the reliable assessment of a tumor's malignant potential is unattainable. In this study, we introduce a universal mathematical model for the differential diagnosis of all morphological types of ACC in adults., Methods: This model was developed by analyzing a retrospective sample of data from 143 patients who underwent histological and immunohistochemical examinations of surgically removed adrenal neoplasms. Statistical analysis was carried out on Python 3.1 in the Google Colab environment. The cutting point was chosen according to Youden's index. Scikit-learn 1.0.2 was used for building the multidimensional model for Python. Logistical regression analysis was executed with L1-regularization, which is an effective method for extracting the most significant features of the model., Results: The new system we have developed is a diagnostically meaningful set of indicators that takes into account a smaller number of criteria from the currently used Weiss scale. To validate the obtained model, we divided the initial sample set into training and test sets in a 9:1 ratio, respectively. The diagnostic algorithm is highly accurate [overall accuracy 100% (95% CI: 96%-100%)]., Discussion: Our method involves determining eight diagnostically significant indicators that enable the calculation of ACC development probability using specified formulas. This approach may potentially enhance diagnostic precision and facilitate improved clinical outcomes in ACC management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Urusova, Porubayeva, Pachuashvili, Elfimova, Beltsevich and Mokrysheva.)

BACKGROUND Primary adrenal epithelioid angiosarcoma (PAEA) is a very uncommon primary adrenal gland tumor that usually occurs around the age of 60 years and is more common among males. Owing to its rarity and histopathological features, PAEA could be misdiagnosed as adrenal cortical adenoma, adrenal cortical carcinoma, or other metastatic cancers, such as metastatic malignant melanoma and epithelioid hemangioendothelioma. CASE REPORT A 59-year-old male patient presented to our hospital with a complaint of abdominal bloating that started 2 months prior. His vital signs and the results of his physical and neurological examinations were unremarkable. A computed tomography scan showed a lobulated mass arising from the hepatic limb of the right adrenal gland but no evidence of metastasis to the chest or abdomen. The patient underwent right adrenalectomy, and the macroscopic pathological findings from a right adrenalectomy specimen revealed atypical tumor cells with an epithelioid appearance in the background of an adrenal cortical adenoma. Immunohistochemical staining was performed to confirm the diagnosis. The final diagnosis was epithelioid angiosarcoma involving the right adrenal gland with a background adrenal cortical adenoma. The patient had no postoperative complications, pain in the surgical wound, or fever. Therefore, he was discharged with a schedule for followup appointments. CONCLUSIONS PAEA may be misinterpreted as adrenal cortical carcinoma, metastatic carcinoma, or malignant melanoma radiologically and histologically. Immunohistochemical stains are essential for diagnosing PAEA. Surgery and strict monitoring are the main treatments. In addition, early diagnosis is essential for patient recovery.

Adrenohepatic fusion (AHF) is a union of the right adrenal gland and the liver with intermingling of parenchymal adrenal and liver cells. The phenomenon can be of clinical importance when evaluating patients with adrenal tumors. Using conventional imaging techniques such as computed tomography, a benign adrenal adenoma developing in an adrenohepatic fusion may mimic an invasive hepatocellular carcinoma or adrenal cortical carcinoma. This study presents a comprehensive review of the literature and shows a prevalence of 5.6 percent in autopsy studies. Moreover, 19 patients with adrenal masses in AHF are presented together with their clinical data.

Here, we aimed to study the important cytokines in plasma to identify the aldosterone-producing adenoma (APA). 19 unilateral primary aldosteronism (UPA) patients and 19 healthy people were divided into UPA group and Control group, and the serum of bilateral adrenal veins and inferior vena cava collected by adrenal blood sampling (AVS) in UPA patients and the serum from the healthy subjects were all used to detect multiple cytokines by Luminex immunoassays. Additionally, The UPA patients subjected to laparoscopic adrenalectomy were divided into different groups by pathological results for further study. According our results, IP-10, CXCL9 and RANTES were significantly higher in UPA group compared with control group, and the combination of the three cytokines have significant predictive power for predicting UPA, while the correlational analyses demonstrated that IP-10 and CXCL9 were positively correlated with BP and HR, while EGF was positively correlated with HDL. Additionally, IL-1b was suggested to be the most potential diagnostic biomarker to discriminate the APA and unilateral adrenal hyperplasia (UAH). The present findings might suggest a possibility of IP-10, CXCL9 and RANTES served as a sign to help UPA diagnosis and finally used to assist the diagnosis of APA, while IL-1b was suggested to be the most potential diagnostic biomarker to identify the APA from the UAH patients., (© 2023. The Author(s).)

While most benign lesions of the adrenal glands represent either an adrenocortical adenoma or a myelolipoma, the advent and frequent use of high-resolution radiological investigations have led to relatively increased incidental discovery of rare adrenal lesions, specifically benign adrenal cysts, adrenal ganglioneuromas, adrenal schwannomas, adrenal hemorrhage, and adrenal calcifications. Radiological characteristics of the different rare benign adrenal lesions could vary from distinct to indeterminate. Though typically nonfunctional, these rare lesions require evaluation for adrenal hormone excess, as they may phenotypically appear similar to pheochromocytoma or adrenocortical carcinoma and could sometimes be associated with or conceal an underlying functional adrenal tumor. In this review, we discuss the various rare benign adrenal lesions, emphasizing a practical perspective., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Preoperative identification of malignant adrenal tumors is challenging. 24-h urinary steroid profiling by LC-MS/MS and machine learning has demonstrated high diagnostic power, but the unavailability of bioinformatic models for public use has limited its routine application. We here aimed to increase usability with a novel classification model for the differentiation of adrenocortical adenoma (ACA) and adrenocortical carcinoma (ACC)., Methods: Eleven steroids (5-pregnenetriol, dehydroepiandrosterone, cortisone, cortisol, α-cortolone, tetrahydro-11-deoxycortisol, etiocholanolone, pregnenolone, pregnanetriol, pregnanediol, and 5-pregnenediol) were quantified by LC-MS/MS in 24-h urine samples from 352 patients with adrenal tumor (281 ACA, 71 ACC). Random forest modelling and decision tree algorithms were applied in training (n = 188) and test sets (n = 80) and independently validated in 84 patients with paired 24-h and spot urine., Results: After examining different models, a decision tree using excretions of only 5-pregnenetriol and tetrahydro-11-deoxycortisol classified three groups with low, intermediate, and high risk for malignancy. 148/217 ACA were classified as being at low, 67 intermediate, and 2 high risk of malignancy. Conversely, none of the ACC demonstrated a low-risk profile leading to a negative predictive value of 100% for malignancy. In the independent validation cohort, the negative predictive value was again 100% in both 24-h urine and spot urine with a positive predictive value of 87.5% and 86.7%, respectively., Conclusions: This simplified LC-MS/MS-based classification model using 24-h-urine provided excellent results for exclusion of ACC and can help to avoid unnecessary surgeries. Analysis of spot urine led to similarly satisfactory results suggesting that cumbersome 24-h urine collection might be dispensable after future validation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: This study aimed to explore the possible pathogenesis of a rare case of co-existing Cushing's syndrome (CS) and primary aldosteronism (PA) caused by bilateral adrenocortical adenomas secreting aldosterone and cortisol, respectively., Methods: A 41-year-old Chinese woman with severe hypertension and hypokalemia for 5 and 2 years, respectively, was referred to our hospital. She had a Cushingoid appearance. Preoperative endocrinological examinations revealed autonomous cortisol and aldosterone secretion. Computed tomography revealed bilateral adrenal adenomas. Subsequently, adrenal vein sampling and sequential left and right partial adrenalectomy indicated the presence of a left aldosterone-producing tumor and a right cortisol-producing tumor. Pathological examination included immunohistochemical analysis of the resected specimens. Secretions of aldosterone and cortisol were observed both in vivo and in vitro . Further, whole-exome sequencing was performed for DNA that was extracted from peripheral blood leukocytes and bilateral adrenal adenomas in order to determine whether the patient had relevant variants associated with PA and CS., Results: Immunohistochemical staining revealed that the left adenoma primarily comprised clear cells expressing CYP11B2, whereas the right adenoma comprised both eosinophilic compact and clear cells expressing CYP11B1. The mRNA levels of steroidogenic enzymes (including CYP11B1 and CYP17A1) were high in the right adenoma, whereas CYP11B2 was highly expressed in the left adenoma. A novel somatic heterozygous missense variant- KCNJ5 c.503T > G (p.L168R)-was detected in the left adrenal adenoma, but no other causative variants associated with PA and CS were detected in the peripheral blood or right adrenocortical adenoma. In the primary cell culture of the resected hyperplastic adrenal adenomas, verapamil and nifedipine, which are two calcium channel blockers, markedly inhibited the secretion of both aldosterone and cortisol., Conclusion: We present an extremely rare case of bilateral adrenocortical adenomas with distinct secretion of aldosterone and cortisol. The heterogeneity of the tumor cell compositions of aldosterone- and cortisol-producing adenoma (A/CPA) and somatic mutation of KCNJ5 may have led to different hormone secretions in the bilateral adrenal adenomas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Wan, Wang, Yang, Liang, Wang and Jin.)

Background: Recent advances in omics techniques have allowed detailed genetic characterization of cortisol-producing adrenal adenoma (CPA). In contrast, the pathophysiology of CPAs has not been elucidated in detail on the level of tumor metabolic alterations., Methods: The current study conducted a comprehensive mass spectrometry imaging (MSI) map of CPAs in relation to clinical phenotypes and immunohistochemical profiles of steroidogenic enzymes. The study cohort comprised 46 patients with adrenal tumors including CPAs (n 35) and nonfunctional adenomas (n 11)., Results: Severity of cortisol hypersecretion was significantly correlated with 29 metabolites (adjusted P 0.05). Adrenal androgens derived from the classic androgen pathway were inversely correlated with both cortisol secretion (rs 0.41, adjusted P 0.035) and CYP11B1 expression (rs 0.77, adjusted P 2.00E-08). The extent of cortisol excess and tumor CYP11B1 expression further correlated with serotonin (rs 0.48 and 0.62, adjusted P 0.008 and 2.41E-05). Tumor size was found to be correlated with abundance of 13 fatty acids (adjusted P 0.05) and negatively associated with 9 polyunsaturated fatty acids including phosphatidic acid 38:8 (rs 0.56, adjusted P 0.009)., Conclusions: MSI reveals novel metabolic links between endocrine function and tumorigenesis, which will further support the understanding of CPA pathophysiology., (© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Adrenocortical adenoma (ADA) and myelolipoma are two common benign neoplasms of the adrenal cortex that have been reported to occur together., Case Report: A 14-year-old girl presented with the features of ACTH-independent endogenous Cushing syndrome. Abdominal CECT revealed a left adrenal 2.3 × 1.8 × 1.5 cm arterially enhancing nodular lesion with central hypodensity. Histologically, this was an ADA with oncocytic change and myelolipomatous differentiation/metaplasia., Discussion/conclusion: ADA with myelolipomatous differentiation/metaplasia can occur in the pediatric age group.

Primary aldosteronism is the most common form of secondary arterial hypertension, due to excessive aldosterone production from the adrenal gland. Although somatic mutations have been identified in aldosterone producing adenoma, the exact mechanisms leading to increased cell proliferation and nodule formation remain to be established. One hypothesis is that changes in vascular supply to the adrenal cortex, due to phenomena of atherosclerosis or high blood pressure, may influence the morphology of the adrenal cortex, resulting in a compensatory growth and nodule formation in response to local hypoxia. In this review, we will summarize our knowledge on the mechanisms regulating adrenal cortex development and function, describe adrenal vascularization in normal and pathological conditions and address the mechanisms allowing the cross-talk between the hormonal and vascular components to allow the extreme tissue plasticity of the adrenal cortex in response to endogenous and exogenous stimuli. We will then address recent evidence suggesting a role for alterations in the vascular compartment that could eventually be involved in nodule formation and the development of primary aldosteronism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abdellatif, Fernandes-Rosa, Boulkroun and Zennaro.)

Abnormalities of the insulin‑like growth factor 2 (IGF2)‑H19 locus with the overexpression of IGF2 are frequent findings in adrenocortical carcinoma (ACC). The present study assessed the expression of RNAs and microRNAs (miRNAs/miRs) from the IGF2‑H19 locus using PCR‑based methods in ACC and adrenocortical adenoma (ACA). The results were associated with proteomics data. IGF2 was overexpressed in ACC, and its expression correlated with that of miR‑483‑3p and miR‑483‑5p hosted by IGF2 . The downregulated expression of H19 in ACC compared to ACA correlated with miR‑675 expression hosted by H19 . Several proteins exhibited an inverse correlation in expression and were predicted as targets of miR‑483‑3p , miR‑483‑5p or miR‑675 . Subsets of these proteins were differentially expressed between ACC and ACA. These included several proteins involved in mitochondrial metabolism. Among the mitochondrial respiratory complexes, complex I and IV were significantly decreased in ACC compared to ACA. The protein expression of NADH:ubiquinone oxidoreductase subunit C1 (NDUFC1), a subunit of mitochondrial respiratory complex I, was further validated as being lower in ACC compared to ACA and normal adrenals. The silencing of miR‑483‑5p increased NDUFC1 protein expression and reduced both oxygen consumption and glycolysis rates. On the whole, the findings of the present study reveal the dysregulation of the IGF2‑H19 locus and mitochondrial respiration in ACC. These findings may provide a basis for the further understanding of the pathogenesis of ACC and may have potential values for diagnostics and treatment.

Purpose: Adrenal incidentalomas are common lesions found on abdominal imaging, most of which are lipid-rich adrenal adenomas. Imaging diagnoses differentiating lipid-poor adrenal adenomas (LPA) from non-adenomas (NA) are presently challenging to perform. The aim of the study was to investigate the diagnostic performance of the relative enhancement ratio parameter in identifying LPA from NA., Methods: We retrospectively evaluated consecutively presenting patients with lipid-poor adrenal lesions (January 2015 to August 2021). Lesions were divided into LPA and NA (including hyperenhancing and hypoenhancing NA). Kruskal-Wallis and Bonferroni tests were used to determine the differences in feature parameters between these three groups. Receiver operating characteristic curve analysis was performed to determine the sensitivity for diagnosing LPA and NA at 95% specificity; the parameters were compared using the McNemar test., Results: A total of 253 patients (mean age, 55 ± 12 years; 135 men), 121 with LPA and 132 with NA, were analyzed herein. The sensitivity (achieved at 95% specificity) of the relative enhancement ratio was higher than that of unenhanced attenuation in differentiating LPA from NA (60% vs. 52%, p = 0.064). The relative enhancement ratio yielded a higher sensitivity than unenhanced attenuation (79% vs. 59%, p < 0.001) in differentiating LPA from hypoenhancing NA, and a lower sensitivity (26% vs. 69%, p < 0.001) in differentiating LPA from hyperenhancing NA., Conclusion: The relative enhancement ratio showed better diagnostic performance than unenhanced attenuation in differentiating LPA from hypoenhancing NA, while simultaneously showing poor diagnostic performance in identifying LPA from all NA., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Context: Due to its rare incidence, molecular features of primary aldosteronism (PA) in young adults are largely unknown. Recently developed targeted mutational analysis identified aldosterone-driver somatic mutations in aldosterone-producing lesions, including aldosterone-producing adenomas (APAs), aldosterone-producing nodules (APNs), and aldosterone-producing micronodules, formerly known as aldosterone-producing cell clusters., Objective: To investigate histologic and genetic characteristics of lateralized PA in young adults., Methods: Formalin-fixed, paraffin-embedded adrenal tissue sections from 74 young patients with lateralized PA (<35 years old) were used for this study. Immunohistochemistry (IHC) for aldosterone synthase (CYP11B2) was performed to define the histopathologic diagnosis. Somatic mutations in aldosterone-producing lesions were further determined by CYP11B2 IHC-guided DNA sequencing., Results: Based on the CYP11B2 IHC results, histopathologic classification was made as follows: 48 APAs, 20 APNs, 2 multiple aldosterone-producing nodules (MAPN), 1 double APN, 1 APA with MAPN, and 2 nonfunctioning adenomas (NFAs). Of 45 APAs with successful sequencing, 43 (96%) had somatic mutations, with KCNJ5 mutations being the most common genetic cause of young-onset APA (35/45, 78%). Of 18 APNs with successful sequencing, all of them harbored somatic mutations, with CACNA1D mutations being the most frequent genetic alteration in young-onset APN (8/18, 44%). Multiple CYP11B2-expressing lesions in patients with MAPN showed several aldosterone-driver mutations. No somatic mutations were identified in NFAs., Conclusion: APA is the most common histologic feature of lateralized PA in young adults. Somatic KCNJ5 mutations are common in APAs, whereas CACNA1D mutations are often seen in APNs in this young PA population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Adrenocortical carcinoma (ACC) is a rare malignant tumor. Genetic abnormalities that may represent therapeutic targets and prognostic factors in ACC remain unclear. Besides being one of the main cellular defense mechanisms that regulates antioxidant pathways for detoxifying reactive oxygen species (ROS), the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) promotes tumor proliferation by increasing metabolic activity. In surgical specimens from 12 cases of nonmetastatic ACCs and nine cases of benign adrenocortical adenoma (ACA), we investigated gene mutation and protein expressions for Nrf2 and the preoperative maximum standard glucose uptake (SUVmax) on [ 18 F]fluorodeoxy-glucose positron emission tomography. Three of five ACCs with a Weiss score of 7 to 9 were Nrf2 mutants; these ACCs had higher expression of Nrf2 and higher preoperative SUVmax. The other seven ACCs had a Weiss score of 3 to 6; these seven ACCs and all the ACAs were non-Nrf2 gene mutants. Patients with a Weiss score of 7 to 9 and Nrf2 mutant ACC had shorter overall survival. Based on Helsinki scoring, three ACCs with a Helsinki score greater than 17 had Nrf2 mutants, higher expression of Nrf2, higher preoperative SUVmax, and shorter overall survival. Our findings indicate that Nrf2 activation and the associated increase in metabolism play roles in ACC, in particular in ACC with a Weiss score of 7 to 9 and a Helsinki score of greater than 17., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: To compare diagnostic accuracy of washout (WO)-CT to chemical shift (CS)-MRI + T2W adrenal MRI Calculator (T2W-Calculator) to diagnose adrenal adenoma in indeterminate adrenal masses., Methods: This retrospective, cross-sectional, non-inferiority study evaluated 40 consecutive indeterminate adrenal masses; each with WO-CT and MRI. Two blinded radiologists independently evaluated in mixed order: pre-contrast attenuation (Hounsfield Units, HU) and absolute WO ([Peak.HU-Delay.HU]/[Peak.HU-Pre.HU] × 100%), Chemical Shift Signal Intensity (CS-SI) Index, T2W SI ratio, and Entropy (which were imputed into the T2W-Calculator). Diagnostic accuracy for adrenal adenoma was tabulated using 2 × 2 tables. True -positive diagnoses of adenoma were CT = Pre-HU < 10 or absolute WO ≥ 60%, MRI = SI index ≥ 16.5% or T2W-Calculator < 0.631., Results: There were 73% (29/40) adenomas and 27% (11/40) other masses (5 pheochromocytoma, 3 solitary fibrous tumor, 1 metastasis, 1 cavernous hemangioma, and 1 adrenocortical carcinoma). Sensitivity, specificity, and accuracy for diagnosis of adenoma using CT-WO were 78% (95% confidence intervals [CI] 56-93%), 35% (14-62%), and 57% (42-71%) Reader 1 and 72% (53-87%), 46% (17-77%), and 59% (41-76%) Reader 2. Sensitivity, specificity, and accuracy for diagnosis of adenoma using MRI were 100% (88-100%), 64% (34-90%), and 82% (67-97%) Reader 1 and 86% (68-96%), 73% (39-94%), and 80% (64-95%) Reader 2. MRI had higher overall accuracy (p = 0.02 Reader 1, 0.05 Reader 2) compared to CT-WO., Conclusion: Chemical shift MRI combined with the T2W adrenal MRI calculator is not inferior to CT Washout for diagnosis of adrenal adenoma among indeterminate adrenal masses., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Knowledge of the exact organ manifestation is essential for a comprehensive understanding of COVID-19 infection. Here, the histopathological changes in the pituitary and adrenal glands were analyzed., Methods: In this series, the formalin-fixed tissues of 63 pituitary glands and 50 adrenal glands were examined. We performed HE and PAS staining and examined COVID-19 nucleocapsid antibody immunohistochemically in the pituitary glands and adrenals., Results: Histologically, there was no evidence of COVID-19-specific changes in the pituitary and adrenal glands. Large pituitary necrosis may be interpreted as a shock reaction. Independent of infection, we found one T-cell lymphoma, two adenomas, and four Rathke-type cysts in the pituitary glands, and 70% of the adrenal glands showed decreased lipid content and an increase in compact cells as a stress response. In addition, a cortical adenoma in one adrenal gland and small cortical nodules in three adrenal glands were detected independently of COVID-19., Conclusion: Pituitary and adrenal glands do not appear histologically predominant in the course of COVID-19., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The new WHO classification of adrenal cortical proliferations reflects translational advances in the fields of endocrine pathology, oncology and molecular biology. By adopting a question-answer framework, this review highlights advances in knowledge of histological features, ancillary studies, and associated genetic findings that increase the understanding of the adrenal cortex pathologies that are now reflected in the 2022 WHO classification. The pathological correlates of adrenal cortical proliferations include diffuse adrenal cortical hyperplasia, adrenal cortical nodular disease, adrenal cortical adenomas and adrenal cortical carcinomas. Understanding germline susceptibility and the clonal-neoplastic nature of individual adrenal cortical nodules in primary bilateral macronodular adrenal cortical disease, and recognition of the clonal-neoplastic nature of incidentally discovered non-functional subcentimeter benign adrenal cortical nodules has led to redefining the spectrum of adrenal cortical nodular disease. As a consequence, the most significant nomenclature change in the field of adrenal cortical pathology involves the refined classification of adrenal cortical nodular disease which now includes (a) sporadic nodular adrenocortical disease, (b) bilateral micronodular adrenal cortical disease, and (c) bilateral macronodular adrenal cortical disease (formerly known primary bilateral macronodular adrenal cortical hyperplasia). This group of clinicopathological entities are reflected in functional adrenal cortical pathologies. Aldosterone producing cortical lesions can be unifocal or multifocal, and may be bilateral with no imaging-detected nodule(s). Furthermore, not all grossly or radiologically identified adrenal cortical lesions may be the source of aldosterone excess. For this reason, the new WHO classification endorses the nomenclature of the HISTALDO classification which uses CYP11B2 immunohistochemistry to identify functional sites of aldosterone production to help predict the risk of bilateral disease in primary aldosteronism. Adrenal cortical carcinomas are subtyped based on their morphological features to include conventional, oncocytic, myxoid, and sarcomatoid subtypes. Although the classic histopathologic criteria for diagnosing adrenal cortical carcinomas have not changed, the 2022 WHO classification underscores the diagnostic and prognostic impact of angioinvasion (vascular invasion) in these tumors. Microscopic angioinvasion is defined as tumor cells invading through a vessel wall and forming a thrombus/fibrin-tumor complex or intravascular tumor cells admixed with platelet thrombus/fibrin. In addition to well-established Weiss and modified Weiss scoring systems, the new WHO classification also expands on the use of other multiparameter diagnostic algorithms (reticulin algorithm, Lin-Weiss-Bisceglia system, and Helsinki scoring system) to assist the workup of adrenal cortical neoplasms in adults. Accordingly, conventional carcinomas can be assessed using all multiparameter diagnostic schemes, whereas oncocytic neoplasms can be assessed using the Lin-Weiss-Bisceglia system, reticulin algorithm and Helsinki scoring system. Pediatric adrenal cortical neoplasms are assessed using the Wieneke system. Most adult adrenal cortical carcinomas show > 5 mitoses per 10 mm 2 and > 5% Ki67. The 2022 WHO classification places an emphasis on an accurate assessment of tumor proliferation rate using both the mitotic count (mitoses per 10 mm 2 ) and Ki67 labeling index which play an essential role in the dynamic risk stratification of affected patients. Low grade carcinomas have mitotic rate of ≤ 20 mitoses per 10 mm 2 , whereas high-grade carcinomas show > 20 mitoses per 10 mm 2 . Ki67-based tumor grading has not been endorsed in the new WHO classification, since the proliferation indices are continuous variables rather than being static thresholds in tumor biology. This new WHO classification emphasizes the role of diagnostic and predictive biomarkers in the workup of adrenal cortical neoplasms. Confirmation of the adrenal cortical origin of a tumor remains a critical requirement when dealing with non-functional lesions in the adrenal gland which may be mistaken for a primary adrenal cortical neoplasm. While SF1 is the most reliable biomarker in the confirmation of adrenal cortical origin, paranuclear IGF2 expression is a useful biomarker in the distinction of malignancy in adrenal cortical neoplasms. In addition to adrenal myelolipoma, the new classification of adrenal cortical tumors has introduced new sections including adrenal ectopia, based on the potential role of such ectopic tissue as a possible source of neoplastic proliferations as well as a potential mimicker of metastatic disease. Adrenal cysts are also discussed in the new classification as they may simulate primary cystic adrenal neoplasms or even adrenal cortical carcinomas in the setting of an adrenal pseudocyst., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Primary adrenal angiosarcoma is a rare, malignant, vascular neoplasm. These neoplasms typically arise in middle age (median age of 60 years) and are more common in males (65%) than in females. Although rare, these neoplasms are aggressive with a propensity for local recurrence and metastasis and a median survival of 18 months. We present 2 cases of primary adrenal angiosarcoma with synchronous, ipsilateral adrenocortical adenomas. We review the cases of adrenal angiosarcoma reported since 1988 and discuss their clinical and histopathologic characteristics.

Objective: Primary aldosteronism (PA) is the commonest cause of endocrine hypertension ranging from 4.6 to 16.6% according to the diagnostic tests employed. The aim of this study was to compare the traditional saline infusion test (SIT) with the modified post-dexamethasone saline infusion test (DSIT) by applying both tests on the same subjects., Methods: We studied 68 patients (72% hypertensives) with single adrenal adenoma and 55 normotensive controls with normal adrenal imaging. Serum cortisol, aldosterone, and plasma renin concentration (PRC) were measured and the aldosterone-to-renin ratio (ARR) was calculated. Using the mean ± 2 s.d. values from the controls, we defined the upper normal limits for cortisol, aldosterone, and PRC for both the SIT and DSIT., Results: In the controls, the post-DSIT aldosterone levels and the ARR were approximately two-fold and three-fold lower, respectively, than the corresponding post-SIT values (all P = 0.001) leading to lower cut-offs of aldosterone suppression. Applying these cut-offs to patients with adrenal adenomas, the prevalence of PA was 13.2% following the SIT and 29.4% following the DSIT, respectively. In addition, 54.5% of patients with PA had concomitant autonomous cortisol secretion (ACS). Targeted treatment of PA resulted in resolution of hypertension and restoration of normal secretory aldosterone dynamics., Conclusions: The DSIT improves the diagnostic accuracy of PA, allowing for the detection of milder forms of PA in patients with adrenal adenomas. This is of particular importance as such patients may be at an increased risk of developing cardiovascular and renal morbidity that could be enhanced in the presence of concomitant ACS.

Objectives: Adrenal adenoma with myelolipomatous degeneration (AMD) is a rarely reported and often overlooked entity. The aim of this study is to improve understanding of these lesions by characterizing the imaging findings with pathologic and clinical correlation., Methods: In the largest series to date, we report 11 nodules in 11 patients confirmed with a pathologic diagnosis of AMD. The available cross-sectional imaging and histopathologic features were reviewed by two radiologists and two pathologists, respectively. Clinical and laboratory data for each patient were obtained from the electronic medical records, when available., Results: All 11 patients had a CT prior to resection or biopsy of the adrenal nodule, with five having received an adrenal mass protocol study. An MRI was available in three patients. The median size of the nodules on imaging was 4.5 cm (range 2.8-8.7) and all but one had macroscopic fat. The largest focus of macroscopic fat had a median size of 0.7 cm (range 0.2-1.6) and on average was 14.4% the size of the tumor, using greatest dimensions. Four (36.4%) patients had a diagnosis of Cushing syndrome prior to nodule resection., Conclusions: Not all adrenal nodules with macroscopic fat on imaging are pure myelolipomas. An AMD should be considered, especially if the foci of fat are small and other features of an adenoma are present. Some may also be associated with Cushing syndrome., Advances in Knowledge: Myelolipomatous degeneration within an adrenal adenoma has only rarely been previously reported with very few reports emphasizing the imaging features. There may be an association with cortisol hypersecretion and improved recognition of this entity could lead to changes in clinical management.

Objective: Adrenal adenomas are frequently picked up incidentally on cross-sectional imaging and are known to have a classic imaging appearance on CT and MRI. However, not all adrenal adenomas have this typical radiologic appearance. Our aim is to present the radiological features of atypical adrenocortical adenomas with pathological correlation., Methods: All the imaging from the pathologically proven adrenal adenoma cases in our hospital (Tallaght University Hospital, Dublin, Ireland) database (from 2004 to 2019) was reviewed. 8 out of 48 cases (16%) had an atypical radiological appearance and were selected for presentation., Results: Eight cases demonstrated atypical radiological features including heterogeneous density, incomplete washout on post-contrast imaging, the presence of macroscopic fat and calcification. Lipomatous metaplasia was present in two of the cases pathologically., Conclusion: Adrenocortical adenomas are the most common adrenal mass encountered on CT, however, may not always have classic imaging features. Radiologists should be familiar with both the typical and atypical imaging manifestations of these benign adrenal lesions., Advances in Knowledge: This paper comprehensively describes the atypical features of adrenocortical adenomas with case examples and radiologic-pathologic correlation. Guidelines and an approach to the work-up of adrenal lesions with atypical appearances are also provided.

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cortisol-producing adrenocortical adenoma (CPA) during pregnancy rarely occurs in clinic. Growing evidence suggests that DNA methylation plays a key role in adrenocortical adenomas. The present study aims to examine the genome-wide DNA methylation profiles and identify the differences in DNA methylation signatures of non-pregnant and pregnant patients with CPA., Results: Four pregnant and twelve non-pregnant patients with CPA were enrolled. The pregnant patients with CPA had higher serum cortisol, Estradiol, Progesterone, and human chorionic gonadotropin concentration, while having lower serum FSH (follicle-stimulating hormone) and luteinizing hormone concentrations (P < 0.01). Compared with the non-pregnant patients, the duration is shorter, and the growth rate of the tumor is faster in pregnant patients with CPA (P < 0.05). Morphology and cell proliferation assay showed that the percentage of Ki-67 positive cells in CPA were higher in pregnant group than non-pregnant group (8.0% vs 5.5%, P < 0.05). The DNA methylation analysis showed that Genome-wide DNA methylation signature difference between pregnant and non-pregnant with CPA, that the pregnant group had more hypermethylated DMPs (67.94% vs 22.16%) and less hypomethylated DMPs (32.93% vs 77.84%). The proportion of hypermethylated DMPs was relatively high on chromosomes 1 (9.68% vs 8.67%) and X (4.99% vs 3.35%) but lower on chromosome 2(7.98% vs 12.92%). In pregnant patients with CPA, 576 hypomethylated DMPs and 1109 hypermethylated DMPs were identified in the DNA promoter region. Bioinformatics analysis indicated that the Wnt/β-Catenin pathway, Ras/MAPK Pathway and PI3K-AKT Pathway were associated with the development of CPA during pregnancy., Conclusions: Genome-wide DNA methylation profiling of CPA in non-pregnant and pregnant patients was identified in the present study. Alterations of DNA methylation were associated with the pathogenesis and exacerbation of CPA during pregnancy., (© 2021. The Author(s).)

[Figure: see text].

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pinto, Rodriguez-Galindo, Lam, Ruiz, Zambetti and Ribeiro.)

The molecular mechanisms by which ATP1A1 mutation-mediated cell proliferation or tumorigenesis in aldosterone-producing adenomas (APAs) have not been elucidated. First, we investigated whether the APA-associated ATP1A1 L104R mutation stimulated cell proliferation. Second, we aimed to clarify the molecular mechanisms by which the ATP1A1 mutation-mediated cell proliferated. We performed transcriptome analysis in APAs with ATP1A1 mutation. ATP1A1 L104R mutation were modulated in human adrenocortical carcinoma (HAC15) cells (ATP1A1-mutant cells), and we evaluated cell proliferation and molecular signaling events. Transcriptome and immunohistochemical analysis showed that Na/K-ATPase (NKA) expressions in ATP1A1 mutated APA were more abundant than those in non-functioning adrenocortical adenoma or KCNJ5 mutated APAs. The significant increase of number of cells, amount of DNA and S-phase population were shown in ATP1A1-mutant cells. Fluo-4 in ATP1A1-mutant cells were significantly increased. Low concentration of ouabain stimulated cell proliferation in ATP1A1-mutant cells. ATP1A1-mutant cells induced Src phosphorylation, and low concentration of ouabain supplementation showed further Src phosphorylation. We demonstrated that NKAs were highly expressed in ATP1A1 mutant APA, and the mutant stimulated cell proliferation and Src phosphorylation in ATP1A1-mutant cells. NKA stimulations would be a risk factor for the progression and development to an ATP1A1 mutant APA.

Somatic mutation in the KCNJ5 gene is a common driver of autonomous aldosterone overproduction in aldosterone-producing adenomas (APA). KCNJ5 mutations contribute to a loss of potassium selectivity, and an inward Na+ current could be detected in cells transfected with mutated KCNJ5. Among 223 unilateral primary aldosteronism (uPA) individuals with a KCNJ5 mutation, we identified 6 adenomas with a KCNJ5 p.Gly387Arg (G387R) mutation, previously unreported in uPA patients. The six uPA patients harboring mutant KCNJ5-G387R were older, had a longer hypertensive history, and had milder elevated preoperative plasma aldosterone levels than those APA patients with more frequently detected KCNJ5 mutations. CYP11B2 immunohistochemical staining was only positive in three adenomas, while the other three had co-existing multiple aldosterone-producing micronodules. The bioinformatics analysis predicted that function of the KCNJ5-G387R mutant channel could be pathological. However, the electrophysiological experiment demonstrated that transfected G387R mutant cells did not have an aberrantly stimulated ion current, with lower CYP11B2 synthesis and aldosterone production, when compared to that of the more frequently detected mutant KCNJ5-L168R transfected cells. In conclusion, mutant KCNJ5-G387R is not a functional KCNJ5 mutation in unilateral PA. Compared with other KCNJ5 mutations, the observed mildly elevated aldosterone expression actually hindered the clinical identification of clinical unilateral PA. The KCNJ5-G387R mutation needs to be distinguished from functional KCNJ5 mutations during genomic analysis in APA evaluation because of its functional silence.

Introduction: Previous studies on the surgical outcomes of aldosterone-producing adenoma (APA) patients were mainly based on the histopathological diagnosis of HE staining or adrenal venous sampling (AVS) instead of the functional pathology. The aim of the present study was to evaluate the surgical outcomes of APA patients based on the functional pathological diagnosis of APA according to HISTALDO (histopathology of primary aldosteronism) consensus., Methods: Clinical data of 137 patients with suspected APA were analyzed retrospectively. All patients had hypertension and spontaneous hypokalemia. In all patients, CT showed a unilateral solitary hypodense adrenal lesion, and a contralateral adrenal gland of normal morphology. Tumors were removed and immunostained for CYP11B2, and their pathology were identified based on HISTALDO consensus. Patients were followed up 6 to 24 months after operation., Results: Among 137 cases of presumptive APA diagnosed by CT, 130 (95%) cases were pathologically diagnosed with classical pathology, including 123 APA(90%) and 7 aldosterone-producing nodule (APN) (5%). 7 cases (5%) had non-functioning adenoma (NFA) with aldosterone-producing micronodule (APM) or multiple aldosterone-producing micronodule (MAPM) in the surrounding adrenal tissue. In all 137 patients, hypertension was complete or partial clinical success postoperatively. Complete clinical success was achieved in 73 (53%), and partial clinical success was achieved in 64 (47%) cases. Serum potassium level recovered to normal in all. In 123 patients with APA, complete clinical success was reached in 67 (54%), and partial clinical success was reached in 56 (46%) cases. Gender, duration of hypertension and the highest SBP were significant independent predictors for cure of APA after surgery. A multiple logistic regression model integrating the three predictors was constructed to predict the outcome, which achieved a sensitivity of 72.4% and a specificity of 73.1%., Conclusion: The specificity of CT in the diagnosis of APA and APN patients with hypokalemia was 95%. All patients achieved complete or partial clinical success after surgery. Gender, duration of hypertension and the highest SBP were independent predictors for the postoperative cure of APA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Wang, Zhang, Wen, Dong, Chang, Sun, Ma, Cui, Chen, Lu, Ren, Tong and Li.)

Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Laparoscopic adrenalectomy is standard treatment for patients with unilateral aldosterone-producing adenomas, but surgeons are increasingly tempted to perform partial adrenalectomy, disregarding potential multinodularity of the adrenal. We assess the diagnostic value of endoscopic ultrasound for differentiating solitary adenomas from multinodularity by examining in-depth adrenal pathology with ex vivo 11.7 T magnetic resonance imaging and immunohistochemistry., Materials and Methods: In 15 primary aldosteronism patients, we performed intraoperative endoscopic ultrasound, ex vivo magnetic resonance imaging and histopathological examination. Every adrenal was intraoperatively and postoperatively assessed for solitary adenomas or multinodular hyperplasia. After unblinding for ex vivo magnetic resonance imaging results a second detailed histopathological examination, including immunohistochemistry analysis with CYP11B2 (aldosterone synthase) and chemokine receptor 4 (CXCR4), a new marker for aldosterone-producing adenomas, was performed. Finally, presence of somatic mutations linked to aldosterone-producing adenomas was assessed., Results: The sensitivity and specificity of endoscopic ultrasound to identify multinodularity were 46% and 50%, respectively. We found multinodular hyperplasia in 87% of adrenals with ex vivo magnetic resonance imaging combined with detailed histopathology, and 6 adrenals contained multiple CYP11B2-producing nodules. Every CYP11B2 positive nodule and 61% of CYP11B2 negative nodules showed CXCR4 staining. Finally, in 4 adrenals (27%) we found somatic mutations. In multinodular glands, only 1 nodule harbored this mutation., Conclusions: Intraoperative endoscopic ultrasound in primary aldosteronism patients has low accuracy to identify multinodularity. Ex vivo magnetic resonance imaging can serve as a tool to direct detailed histopathological examination, which frequently shows CYP11B2 production in multiple nodules. Therefore, partial adrenalectomy is inappropriate in primary aldosteronism as multiple aldosterone-producing nodules easily stay behind.