Benign Adrenocortical Adenomas Research Articles

Mild autonomous cortisol secretion: pathophysiology, comorbidities and management approaches.

The majority of incidentally discovered adrenal tumours are benign adrenocortical adenomas and the prevalence of adrenocortical adenomas is around 1-7% on cross-sectional abdominal imaging. These can be non-functioning adrenal tumours or they can be associated with autonomous cortisol secretion on a spectrum that ranges from rare clinically overt adrenal Cushing syndrome to the much more prevalent mild autonomous cortisol secretion (MACS) without signs of Cushing syndrome. MACS is diagnosed (based on an abnormal overnight dexamethasone suppression test) in 20-50% of patients with adrenal adenomas. MACS is associated with cardiovascular morbidity, frailty, fragility fractures, decreased quality of life and increased mortality. Management of MACS should be individualized based on patient characteristics and includes adrenalectomy or conservative follow-up with treatment of associated comorbidities. Identifying patients with MACS who are most likely to benefit from adrenalectomy is challenging, as adrenalectomy results in improvement of cardiovascular morbidity in some, but not all, patients with MACS. Of note, diagnosis and management of patients with bilateral MACS is especially challenging. Current gaps in MACS clinical practice include a lack of specific biomarkers diagnostic of MACS-related health outcomes and a paucity of clinical trials demonstrating the efficacy of adrenalectomy on comorbidities associated with MACS. In addition, little evidence exists to demonstrate the efficacy and safety of long-term medical therapy in patients with MACS.

FRI192 Serum Steroid Biomarkers For The Differential Diagnosis Of Adrenocortical Carcinoma (ACC) And Adrenocortical Adenoma (ACA)

Abstract Disclosure: D. van Rooyen: None. R. Scheske: None. A.M. Lerario: None. W.E. Rainey: None. R.J. Auchus: None. G.D. Hammer: None. T. Else: None. Background: Adrenal tumors are very common, with the vast majority being benign adrenocortical adenomas (ACA). Adrenocortical carcinomas (ACC) represent only a very small proportion of adrenal tumors. Distinction between the common ACA and rare ACC relies on invasive and costly protocols which are often inconclusive. Research into the use of steroid biomarkers as a non-invasive alternative diagnostic tool has been the focus of various steroid metabolomics studies. In this study, we aimed to identify serum steroid biomarkers to distinguish ACA from ACC. Methods: This study population was comprised of 103 patient samples, including 45 (31 female) and 58 (40 female) respective samples from ACA (age 32-90) and ACC (age 16-77) patients presenting with disease at the time of sampling. No ACC patients studied had been treated with mitotane. Serum steroid levels (4 sulfates and 25 Δ4 steroids) were measured using liquid-chromatography tandem mass spectrometry (LCMS/MS) with comparisons made between steroid profiles in ACA vs ACC and between males and females within each group (ACA and ACC). Data were analyzed to obtain the geometric means with 95% CIs, and statistical significance was determined using a two-tailed Mann-Whitney test. Results: ACC patients were characterized by significantly elevated levels of pregnenolone-sulfate, 17hydroxypregnenolone-sulfate, 11-deoxycorticosterone, 17hydroxyprogesterone, and androstenedione when compared to ACA patients. In addition, steroid levels differed between male and female samples, with dehydroepiandrosterone-sulfate (p<0.01), androstenediol-3-sulfate (p<0.05), 11deoxycortisol (p<0.0001), cortisol (p<0.05) and testosterone (p<0.01) significantly increased in female ACC patients when compared to male counterparts. Conclusion: Significant differences in plasma steroids were observed in ACC vs ACA patients, with more steroids altered in female patients. Serum steroid profiles, particularly steroid sulfates, might serve as an adjunct, easy to obtain diagnostic tool to differentiate ACA and ACC. Presentation: Friday, June 16, 2023

PSAT017 A Case of Aldosterone- and Cortisol Co-secreting Adrenal Corticol Neoplasm with Lipomatous and Myeiolipomatous Metaplasia

Abstract Background Adrenal lipomatous tumors are uncommon fatty tumors of theadrenal glands with myelolipoma being the most common histologic feature.Adrenal myelolipoma is a benign adrenal cortical neoplasm composed of fat andmyeloid tissue, commonly diagnosed if fat composition of tumor is more than 50% on cross-sectional imaging studies. The myelolipomatous metaplasia is asecondary degenerative change in primary adrenal tumor, usually seen in benignadrenocortical adenomas and rarely in adrenocortical carcinomas and corticalneoplasms of uncertain malignant potential. Adrenocortical neoplasms areclassified as benign or malignant based on modified Weiss score, when the criteriaare not clear, the tumor is classified as a neoplasm of uncertain malignant lesion.As adrenal lipomatous tumors are usually benign and non-functional, patients withthese tumors often do not undergo hormonal evaluation. Clinical Case A 58-year-old female with a history of hypertension diagnosed atage 35 years, on five antihypertensive agents and a history of intermittentspontaneous hypokalemia, was found to have a 6 cm left adrenal myelolipoma onnon-contrast computed tomography of the abdomen performed when she presentedfor left flank pain due to nephrolithiasis. The biochemical evaluation showedpotassium of 2.8 meq/l, plasma aldosterone of 65.9 ng/dl with plasma renin activityof 0.1 ng/ml/hr. An overnight 1 mg dexamethasone suppression test showed nonsuppressible serum cortisol of 10.8 μg/dl. DHEAS, and ACTH were measured at24.5 μg/dl and <5 pg/ml, respectively. Left adrenalectomy was performed and onthe following day, morning serum cortisol was 2.3 μg/dl with aldosterone of 6.2ng/dl and plasma renin activity of 4.2 ng/ml/hr. Expectedly patient beganexperiencing nausea, and postural dizziness. Patient systolic blood pressure was inlow100 mmHg. Thus, hydrocortisone therapy was initiated. Immediatelypostoperatively and thereafter, her blood pressure was controlled with noantihypertensive agent, and morning cortisol measured without hydrocortisone for∼36 h remained low at 1.2 μg/dL. Pathology showed adrenal cortical neoplasm ofuncertain malignant potential with associated lipomatous and myelolipomatousmetaplasia without atypical mitoses, or lymphovascular invasion, or necrosis, orcapsular invasion, with negative surgical margins. Although mitotic activity in thetumor is lacking, the tumor was designated uncertain malignant potential due to thelarge size (7 cm), and lack of clear cells < 25% according to modified Weiss score. Conclusion We report a rare case of aldosterone and cortisol co-secreting adrenalcortical neoplasm of uncertain malignant potential with lipomatous andmyelolipomatous metaplasia. While the majority of cases of myelolipoma arebenign and non-functioning, this case emphasizes the importance of looking forsymptoms and signs pointing to adrenal hyperfunction, thorough hormonal andmorphologic evaluation and, definitive treatment is curative unilateraladrenalectomy. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSAT024 A Case of Mild Autonomous Cortisol Secretion Managed with Active Surveillance

Abstract Mild autonomous cortisol secretion is characterized by the failure to suppress cortisol sufficiently after dexamethasone administration but without the stigmata of overt Cushing's syndrome. This condition, diagnosed in up to 50% of adrenal incidentalomas, has low overall rates of progression and mild cases can present a treatment dilemma. Here we describe one such case of cortisol excess well managed with a surveillance strategy rather than surgical intervention. A 49-year-old female with a past medical history of hypothyroidism was evaluated in the endocrine clinic for an incidental adrenal mass. CT imaging revealed a 2.7 cm left adrenal nodule, stable in size compared to prior imaging, with features typical of benign adrenocortical adenoma. Initial 1 mg DST with 8 am cortisol of 11.7µg/dl. Late night salivary cortisol (LNSC)level was found to be elevated at 130 ng/dl (nl<100 ng/dL). At that time, 24-hour urine free cortisol (UFC) was found to be borderline at 23.98 µg/day (nl<24 µg/day). Further testing at 6 months and 1 year from initial assessment showed persistently elevated LNSC level (110 ng/dL) and stable 24-hour UFC at 24 µg/day. Morning ACTH level was 19 pg/mL. One year after initial assessment, LNSC continued to be elevated at 0.106 µg/dL (nl <0.010–0.090 µg/dL) and repeat overnight 1 mg DST with 8am cortisol was unsuppressed at 10 mcg/dL representing at least two years of autonomous, mildly elevated cortisol levels. DHEA-S was low at 13.6 µg/dl (41.2 - 243.7 µg/dL). She had no history of diabetes, hypertension, obesity, hyperlipidemia or clinical osteoporosis. Her social history was negative for tobacco or alcohol abuse. Repeated physical exams were within normal limits, and she did not have any signs of central adiposity, abdominal striae, thinning of skin or hirsutism. She continued to deny any subjective symptoms of lethargy or muscle weakness. Given low normal range ACTH values, mildly increased midnight salivary cortisol, failure to suppress after 1 mg overnight DST with no clinical evidence of overt hypercortisolism, patient was diagnosed with mild autonomous cortisol secretion. She did not show any signs of hypertension, hyperglycemia or physical changes that would warrant concern for hypercortisolemic end organ effects. As the patient was largely asymptomatic, with stable CT imaging of left adrenal adenoma, left adrenalectomy was discussed but not recommended as patient preferred an observation surveillance strategy with laboratory evaluation every 6 months to monitor for hypercortisolemia. This case demonstrates that a surveillance strategy, rather than surgery, may be appropriate in selected cases of mild autonomous cortisol secretion from an incidentally discovered adrenocortical adenoma, especially when end organ effects of cortisol excess are clinically absent. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Pediatric adrenal incidentaloma as a rare and difficult to diagnose finding - review

Adrenal incidentaloma (AI) is an asymptomatic mass localized in the adrenal gland, usually detected during diagnostic imaging performed due to other health issues than the suspected adrenal disease. It occurs in 2% of adults and 0,2% of children. Pediatric AI may cause many difficulties in the diagnostic processes. Neuroblastoma is one of the most common malignant tumors in children. Usually, it is localized in the medulla of the adrenal gland. Many patients do not have any symptoms, but some may present with fever, weariness, weight loss, pain, enlarging mass, etc. The majority of cases are high- risk and the survival rate is less than 50%. The diagnostic protocol consists of laboratory tests and radiological imagining. Treatment depends on the risk group that the patient is assigned to. Pheochromocytoma is a rare catecholamine-secreting tumor in children originating in the adrenal medulla. Most pediatric patients present with sustained hypertension. 60% of pheochromocytoma cases are sporadic. The surgical removal of the tumor through adrenalectomy is a standard procedure. To the group of pediatric adrenocortical tumors (ACT), benign adrenocortical adenoma (ACA) and malignant adrenocortical carcinoma (ACC) are included. ACA is found in only 20% of cases of ACT. Most of the patients present with signs of virilization, Cushing Syndrome, or both. The 5-years survival rate of ACC in the pediatric population is 46-55%. An adrenal incidentaloma is an unpredictable and possibly dangerous disorder in the pediatric population. Due to the rarity of the finding and their variety, there is not much data and clear recommendations about AI management. Doctors need to know about the prevalence of different types of adrenal tumors in the pediatric population based on age.

Commentary on Adrenal wash-out CT: moderate diagnostic value in distinguishing benign from malignant masses.

The increasing use of cross-sectional imaging, mainly CT, results in an accelerating number of incidental findings, for instance of adrenal tumours. Although most 'adrenal incidentalomas' are benign, it is important to identify the malignant and the hormone producing (functional) tumours. For a small fraction of adrenal incidentalomas, the diagnosis is apparent on imaging, but the large majority requires radiological characterisation. To this end, a previous joint European Society of Endocrinology and European Network for the Study of Adrenal Tumours publication in this jounal, recommends CT measurements of the native (non-contrast) tumour attenuation ≤10 Hounsfield units, consistent with a lipid-rich benign adrenocortical adenoma, and imaging at least 6 months apart, on which unchanged tumour size implies a benign tumour. Because of weak evidence, calculation of CT contrast medium washout was not recommended as a means for tumour characterisation, but this technique has nevertheless still been applied in several countries. The recent article by Schloetelburg et al. in this journal is important because, in the largest study to date, the authors confirm that calculation of CT contrast medium washout with established thresholds is insufficient to reliably characterise adrenal tumours. Their results are therefore expected to impact the management of these patients.

Association of Nrf2 expression and mutation with Weiss and Helsinki scores in adrenocortical carcinoma.

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 [18F]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.

Characteristics of benign adrenocortical adenomas with 18F-FDG PET accumulation.

Although 18F-FDG PET was originally developed to evaluate benign and malignant tumors, the frequency of detection of benign adrenocortical adenomas showing FDG-PET accumulation has increased. However, the details of FDG-PET-accumulated benign adrenocortical adenomas have not been elucidated. To elucidate the pathophysiology of FDG-PET-positive cortisol-producing adrenal tumors, we performed clinicopathological and genetic analyses of adrenocortical adenomas examing FDG-PET in 30 operated patients with unilateral cortisol-producing adrenal tumors (26 adrenal adenomas and 4 adrenal cancers). All adrenocortical carcinomas and 17/26 (65%) benign adrenocortical adenomas showed high FDG accumulation (SUVmax ≥ 3). In adrenocortical adenomas with high FDG accumulation (SUVmax ≥ 3), SUVmax showed a positive correlation with the CT Hounsfield units. A higher SUVmax showed a clear black adenoma appearance with predominantly compact cells, which exhibited high T1 and T2 signals, a lack of signal drop on out-of-phase imaging on MRI, and less accumulation on 131-I adsterol scintigraphy. Furthermore, RNA-sequencing analysis revealed significant increases in the lysosomal and autophagy pathways and metabolic pathways, including glycolysis through glucose transporter (GLUT) 1 and 3, in black adenomas with high-level FDG accumulation. A black adenoma is blackish due to lipofuscin, which accumulates as a result of damaged mitochondria or proteins that escape lysosomal degradation or autophagy. Since FDG in PET is taken up via GLUTs, alteration of the intracellular metabolic dynamics associated with mitochondrial damage in black adenomas may increase PET accumulation. Black adrenal adenomas should be considered with adrenal tumors showing PET accumulation and low lipid contents.

Abstract No. 191 Adrenal venous sampling for lateralization of cortisol hypersecretion in patients with adrenocorticotropic hormone–independent Cushing syndrome and bilateral adrenal masses

To evaluate adrenal venous sampling (AVS) in guiding surgical management of patients with adrenocorticotropic hormone (ACTH) independent Cushing syndrome (CS) and bilateral adrenal masses 28 patients with bilateral adrenal masses and ACTH independent autonomous cortisol secretion who underwent AVS from January 1, 2008, to August 1, 2020, were identified. Methodology and data interpretation were performed as previously described. Cortisol and epinephrine levels were measured from each adrenal vein (AV) and the inferior vena cava (IVC). AVS was technically successful if plasma epinephrine concentration in AV-IVC was > 100 pg/mL. AV/IVC cortisol ratio for each adrenal gland and cortisol lateralization ratio (CLR) were calculated. Previously described parameters were utilized for interpretation: AV/IVC cortisol ratio of > 6.5 on one side and ≤3.3 on the contralateral side with CLR ≥ 2.3 was consistent with a unilateral cortisol-secreting adenoma whereas bilateral AV/IVC cortisol ≥ 4.1 with CLR < 2 was consistent with bilateral cortisol hypersecretion. Clinical, imaging, laboratory, pathology and follow-up data were collected. Primary outcome measure was hypercortisolism recurrence. 28 patients underwent AVS. Patients underwent subsequent right (n = 12) or left (n = 9) total, right total and left partial (n = 1) or bilateral total (n = 3) adrenalectomy. 3 patients were recommended adrenalectomy but were lost to follow up and not included in outcome analysis. Initial presentation included incidental adrenal masses (12%), subclinical CS (64%), overt CS (24%). Sequela included hypertension (88%), osteoporosis/osteopenia (38%), diabetes mellitus (36%), hyperlipidemia (56%), weight gain (76%), depression (52%). AVS was successful in all 28 patients. Data were interpreted as described above to guide laterality of adrenalectomy. Mean AV/IVC cortisol for unilateral adrenalectomies was 12 with mean CLR 3.7. Mean AV/IVC for bilateral adrenalectomies was 8.67 right and 6.33 left with CLR 0.76. Among 29 resected adrenal glands, pathology demonstrated benign adrenocortical adenomas (52%) and macronodular hyperplasia (48%) and mean dominant nodule maximum diameter of 2.7cm and mean weight of 18.2g. At a mean follow-up of 21.8 months, there was no clinical or biochemical recurrence of ACTH-independent hypercortisolism with most recent cortisol of 12.8 ± 7.5 mcg/dL and ACTH of 19.7 ± 13.1 pg/mL. AVS can be used to guide surgical management in patients with ACTH independent Cushing syndrome and bilateral adrenal masses, with favorable midterm outcomes.

Sum of High-Risk Gene Mutation (SHGM): A Novel Attempt to Assist Differential Diagnosis for Adrenocortical Carcinoma with Benign Adenoma, Based on Detection of Mutations of Nine Target Genes

There has been no research on applying gene detection to differential diagnosis of adrenocortical carcinoma (ACC). We attempted to explore a novel auxiliary method for differential diagnosis between ACC with benign adrenocortical adenoma (ACA), based on mutations of target genes in tissues. Nine genes were chosen as target genes, including TP53, CTNNB1, ARMC5, PRKAR1A, ZNRF3, RB1, APC, MEN1, and RPL22. Exons sequencing of target genes were performed in 98 cases of tissue samples by FastTarget technology, including 41 ACC tissues, 32 ACA tissues, and 25 normal adrenal gland tissues. Significant mutations were detected and identified, and the clinical information was collected, for further comparative analysis and application to assist differential diagnosis of ACC. We identified 132 significant gene mutations and 227 significant mutation sites in 37 ACC tissues, much more than ACA and normal adrenal gland tissues. Mutation rates of 6 genes in ACC tissues were obviously higher than ACA tissues, including ZNRF3, ARMC5, TP53, APC, RB1, and PRKAR1A, regarded as high-risk genes. The sum of mutated high-risk genes detected in each sample was denominated sum of high-risk gene mutation (SHGM), and the rates of SHGM > 0 and SHGM > 1 in ACC tissues were 73.0% and 62.2%, respectively, both obviously higher than those in ACA tissues, with significant statistic differences. Especially for 8 cases of ACC with diameter < 5 cm, SHGM > 0 and SHGM > 1 were found in 6 samples (75%) and 4 samples (50%), respectively. However, no relevance was found between SHGM and clinical characteristics of ACC. We identified 6 high-risk genes in ACC tissues, with significantly higher mutation rates than ACA or normal adrenal gland tissues. The sum of mutated high-risk genes detected in ACC tissues was denominated SHGM, which was potential to assist the differential diagnosis of ACC with ACA, especially for the small-size ACC.

β-catenin in adrenal zonation and disease

The Wnt signaling pathway is a critical mediator of the development and maintenance of several tissues. The adrenal cortex is highly dependent upon Wnt/β-catenin signaling for proper zonation and endocrine function. Adrenocortical cells emerge in the peripheral capsule and subcapsular cortex of the gland as progenitor cells that centripetally differentiate into steroid hormone-producing cells of three functionally distinct concentric zones that respond robustly to various endocrine stimuli. Wnt/β-catenin signaling mediates adrenocortical progenitor cell fate and tissue renewal to maintain the gland throughout life. Aberrant Wnt/β-catenin signaling contributes to various adrenal disorders of steroid production and growth that range from hypofunction and hypoplasia to hyperfunction, hyperplasia, benign adrenocortical adenomas, and malignant adrenocortical carcinomas. Great strides have been made in defining the molecular underpinnings of adrenocortical homeostasis and disease, including the interplay between the capsule and cortex, critical components involved in maintaining the adrenocortical Wnt/β-catenin signaling gradient, and new targets in adrenal cancer. This review seeks to examine these and other recent advancements in understanding adrenocortical Wnt/β-catenin signaling and how this knowledge can inform therapeutic options for adrenal disease.

A Critical Analysis of Computed Tomography Washout in Lipid-Poor Adrenal Incidentalomas.

Contrast-enhanced computed tomography (CT) with washout has emerged as an option to distinguish lipid-poor adenomas from non-adenomas. The aim of this study was to assess the utility of CT washout in characterizing indeterminate lipid-poor adrenal incidentalomas. From an Institutional Review Board-approved database, patients with adrenal incidentalomas who had adrenal protocol CT scans with a 15-min washout between 2003 and 2019 were identified. Non-contrast CT attenuation and washout patterns of different tumor types were compared. Overall, 156 patients with 175 adrenal lesions were included. Average tumor size was 3.0cm, non-contrast CT density was 24.7 Hounsfield units (HU), and absolute washout was 52.6%. In 102 lesions (58.3%), CT washout was ≥ 60%; 94 (92.2%) of these were benign adrenocortical adenomas, 7 (6.9%) were pheochromocytomas, and 1 (0.9%) was an adrenal hematoma. Furthermore, in 73 tumors (41.7%), CT washout was < 60%; diagnosis was benign adrenocortical adenoma in 45 (61.6%) lesions, pheochromocytoma in 8 (11%) lesions, metastasis in 9 (12.3%) lesions, adrenocortical cancer in 6 (8.2%) lesions, and 'others' in 5 (6.9%) lesions. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracyof > 60% absolute CT washout for detecting an adrenal adenoma was 67.6%, 77.8%, 92.2%, 38.4%, and 69.7%, respectively. CT washout should be incorporated into the management algorithm of indeterminate adrenal incidentalomas with a high non-contrast CT attenuation to 'rule-in' benign tumors. For small tumors with mild elevation of plasma metanephrines, it should be kept in mind that adenomas and pheochromocytomas may have similar imaging and washout characteristics.

DNA Methylation of Steroidogenic Enzymes in Benign Adrenocortical Tumors: New Insights in Aldosterone-Producing Adenomas.

DNA methylation has been identified among putative regulatory mechanisms for CYP11B2 expression in primary aldosteronism. The objective of this work is to investigate DNA methylation and expression of genes encoding steroidogenic enzymes in benign adrenocortical tumors. This cross-sectional study took place at university hospitals. We collected fresh-frozen tissues from patients with benign adrenocortical adenomas (n = 48) (nonfunctioning n = 9, autonomous cortisol secretion n = 9, Cushing syndrome n = 17, aldosterone-producing [APA] n = 13) and adrenal cortex adjacent to APA (n = 12). We collected formalin-fixed, paraffin-embedded (FFPE) specimens of paired APA and concurrent aldosterone-producing cell clusters (APCCs) (n = 6). DNA methylation levels were evaluated by quantitative bisulfite next-generation sequencing in fresh-frozen tissues (CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, HSD3B1, HSD3B2, NR5A1, STAR, and TSPO) and FFPE APA/APCC paired samples (CYP11B2). CYP11B1, CYP11B2, CYP17, CYP21, and STAR gene expressions were examined by quantitative real-time polymerase chain reaction. The main outcome measure was DNA methylation. CYP11B2 methylation levels were significantly lower in APA than in other adrenal tissues (P < .001). Methylation levels of the remaining genes were comparable among groups. Overall, CYP11B2 expression and DNA methylation were negatively correlated (ρ = -0.379; P = .003). In FFPE-paired APA/APCC samples, CYP11B2 methylation level was significantly lower in APA than in concurrent APCCs (P = .028). DNA methylation plays a regulatory role for CYP11B2 expression and may contribute to aldosterone hypersecretion in APA. Lower CYP11B2 methylation levels in APA than in APCCs may suggest an APCC-to-APA switch via progressive CYP11B2 demethylation. Conversely, DNA methylation seems not to be relevant in regulating the expression of genes encoding steroidogenic enzymes other than CYP11B2.

SAT-172 FDG PET/CT in Benign vs. Malignant Adrenocortical Tumors

18F-fluorodeoxyglucose positron emission tomography computed tomography (FDG PET/CT) is frequently used for evaluation of indeterminate adrenal nodules.The objective of this study was to evaluate the diagnostic performance of FDG PET/CT in distinguishing benign adrenocortical adenomas (ACA) from adrenocortical carcinoma (ACC).We identified 139 patients in our institution who completed both FDG PET/CT and adrenal biopsy or adrenalectomy from 2001 to 2019 using the institutional Electronic Medical Record Search Engine (EMERSE). Patients with adrenal pathology revealing non-adrenocortical tumors were excluded. The imaging characteristics of ACAs were compared with ACCs.Sixteen patients with ACAs and 50 patients with ACC were identified; of the latter, 30 were excluded, because FDG PET/CT imaging was completed after adrenalectomy. The average age of the ACC vs. ACA group was 48±14 and 52±17 years, respectively, with a gender composition of 35% and 25% men, respectively. All 20 patients with ACC had FDG avid lesions, defined by imaging report and increased ratio of adrenal tumor maximum standardized uptake value (SUVmax) to hepatic parenchymal average SUV (SUVmean) of greater than 2.5. Among those with ACAs, 11 had positive, 1 had mildly positive, 3 had indeterminate, and 1 had negative FDG PET/CT findings according to the report. Ratio of adrenal SUVmax to hepatic SUVmean was greater in ACC compared to ACA (13.5 versus 1.6, respectively, p = 0.13), but did not reach statistical significance, likely due to the small sample size and unavailability of SUV ratios for all lesions.Our study identified a large number of ACAs that were deemed FDG avid but without adrenal SUVmax to hepatic SUVmean ratio of greater than 2.5. Although the sensitivity, and therefore the negative predictive value, of FDG PET/CT scan is excellent for the diagnosis of ACC, our data does not allow for the calculation of specificity. This is due to the selection bias inherent in our patient population referred for evaluation of unusual adrenal masses, and the fact that ACAs with negative FDG PET/CT often do not undergo surgery or biopsy, and therefore pathology results are not available. Despite this limitation, our findings show that calculation of the ratio of adrenal SUVmax to hepatic SUVmean, rather than lesion SUVmax alone, helps for characterization of adrenal lesions as malignant vs. benign, and that a negative FDG PET/CT is valuable in excluding ACC.

Adrenal incidentaloma: cardiovascular and metabolic effects of mild cortisol excess.

In the vast majority of cases adrenal incidentalomas (AI) are benign adrenocortical adenomas. They are present in up to 10% of the population over 70 years, with incidence increasing with age. Mild cortisol excess (MCE) in the context of AI is defined as autonomous cortisol secretion (ACS) in the absence of the classical clinical features of Cushing's syndrome. MCE has been reported in up to at least one third of patients with AI. Numerous studies have shown that MCE in AI is associated with increased cardiovascular events and mortality, likely to be consequent upon both hemodynamic changes and inflammatory pathways, and a worse metabolic phenotype characterized by: pancreatic β-cell dysfunction, insulin resistance, visceral obesity and dyslipidemia. There is currently no level 3 evidence from large intervention randomized controlled trials to guide management of MCE in AI, and there is a lack of predictive tools to allow stratification to intervention of only those patients who would benefit in terms of improved metabolic and cardiovascular end-points. Here, we describe the mal-effects of cortisol on cardiovascular and metabolic tissues and discuss management strategies based on current largely observational data.

Subclinical Cushing’s syndrome, renal carcinoma, adrenal adenoma, adrenal incidentaloma.

Patients with renal malignancies present high risk of adrenal hyperplasia and adenoma, and part of these are primary lesions, mostly non-functional. Here we presented a case diagnosed as primary adrenal adenoma with autonomous cortisol secretion accompanied by homolateral renal cell carcinoma. A 79-year-old woman was referred for evaluation of a left adrenal mass, with a past medical history of severe hypertension, diabetes, and hyperlipidemia. On examination, no clinical signs of cushingoid features were found. Biochemical measurements showed plasma cortisol was 12.77 μg/dL and was not suppressed by 1 mg dexamethasone (DXM) overnight test (13.6 μg/dL). The contrast CT scan presented a 2.2 cm diameter adrenal mass and revealed, unfortunately, a hyperdense mass at the middle-upper pole of the left kidney. Laparoscopic nephrectomy with left adrenalectomy was performed and pathological examination indicated a final diagnosis of benign adrenocortical adenoma and renal clear cell carcinoma. At 2 months postoperatively, without replacement treatment of cortisol, a recovery of circadian rhythm of cortisol secretion was detected, indicated recovery of the hypothalamic-pituitary-adrenal axis. Patients with renal cancer might be accompanied with functional adrenal adenoma. Therefore, screening for adrenal function should be recommended in patients with renal tumors and/or adrenal incidentaloma.

SUN-352 Estrogen, Progesterone, and Androgen Receptor Expressions Predict the Prognosis for Adrenocortical Carcinoma

Aim: Adrenocortical carcinoma (ACC) is a rare but mortal endocrine malignancy. While expression of sex steroid receptors is well-known to be associated with tumor prognosis and treatment response in a number of hormone sensitive cancers, sex steroid receptor expression in ACC is not revealed in this context. The aim of this study is to assess prognostic implications of sex steroid receptor expression in ACCs. Method: Paraffin-embedded blocks of 16 ACC cases (8 F, 8 M, mean age 47.9±13.9) and 22 benign adrenocortical adenoma (ACA) cases (14 F, 8 M, mean age 50.0±11.4) who were undergone surgery in our center between 1998-2017 were examined in this case-control study. Estrogen (ER, Leica), androgen (AR, CellMarque) and progesterone receptor (PR, Leica) expressions in both tumor and peritumoral adrenal tissue were semi-quantitatively scored by immunohistochemistry (IHC), by an endocrine pathology specialist. The relationship between the histopathological prognostic indicators, the clinical course of patients and intra-tumor and peritumoral sex steroid receptor expression status were examined. Results: ER and AR expressions of ACCs were significantly higher, while all ACAs were ER and AR negative (ER 25% vs 0%, p=0.014; AR 31% vs 0%, p=0.005). PR expression was similar between groups; although, higher rate of PR expression was observed in ACAs (75% vs 86%, p=0.38). While peri-tumoral adrenal tissue of ACC cases did not express none of the three sex steroid receptors, IHC staining of peripheral adrenal tissue of ACAs revealed positivity for ER, AR and PR (p values <0.005). ACC cases which were negative for ER, PR and/or AR had larger tumor size (r=-0.6, p=0.015). Tumor stage was more advanced in AR negative ACCs (r=-0.6, p=0.021). Progression free survival was shorter in ACC cases which were positive for PR (15 vs 57.5 months, p=0.07); while it was longer in cases peritumoral adrenal tissue was positive for either of three sex steroid receptors (r=0.81, p=0.008). Conclusions: For the first time in this study, expression of sex steroid receptors has been shown to be related with ACC prognosis and clinical/histopathological behaviour.

A rare case of pure testosterone-secreting adrenal adenoma in a postmenopausal elderly woman

BackgroundHyperandrogenemia is more common in puberty and reproductive age, but relatively rare in postmenopausal women. Postmenopausal virilization may result from androgen-producing tumors. Androgen-secreting adrenal tumors are rare in clinical practice and are diagnosed as adrenocortical carcinoma, most of which can co-secrete androgen and cortisol. Highly elevated serum testosterone level with normal adrenal androgens such as dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and androstenedione is usually regarded as ovary origin. Here we describe an unusual case of a postmenopausal woman with markedly elevated serum testosterone level, while DHEAS, androstenedione, 17-hydroxyprogesterone and cortisol were within the normal range.Case presentationA 67-year-old postmenopausal woman with hirsutism in the upper lip and armpit, accompanied by clitoromegaly for 5 months. Hormonal evaluation showed markedly elevated serum testosterone level (714.8 ng/ml), whereas DHEAS, androstenedione, 17-hydroxyprogesterone, and cortisol were within the normal range. Imaging examination showed a mass of 1.5 cm in diameter in the left adrenal gland and normal appearance of both ovaries. PET-CT indicated that it was a case of benign adrenal adenoma and excluded ovarian abnormalities and other ectopic tumors. Thus, a pure testosterone-secreting adrenal tumor was suspected and then adrenalectomy was performed. Histology and immunohistochemistry furtherly confirmed the benign adrenocortical adenoma with immunohistochemistry positive for inhibin α, melan A, β-captenin, SYN (focal), Ki-67(< 3%), and negative for chromogranin (CgA), cytokeratin (CK), S-100, P53. After surgery, the level of testosterone returned to normal range and the clinical symptoms also subsided.ConclusionsPure testosterone-secreting adrenal adenomas are extremely rare, but it can induce severe hyperandrogenism and virilization. The source identification of hyperandrogenemia only based on the levels of testosterone, DHEAS and androstenedione is limited. It is important to evaluate not only ovaries but also adrenals in all women with virilization particularly during menopause, even their androstenedione, DHEA and DHEAS level are normal.

Adrenocortical incidentalomas and bone: from molecular insights to clinical perspectives.

Adrenal incidentalomas constitute a common clinical problem with an overall prevalence of around 2-3%, but are more common with advancing age being present in 10% of those aged 70 years. The majority of these lesions are benign adrenocortical adenomas (80%), characterized in 10-40% of the cases by autonomous cortisol hypersecretion, and in 1-10% by aldosterone hypersecretion. Several observational studies have shown that autonomous cortisol and aldosterone hypersecretion are more prevalent than expected in patients with osteopenia and osteoporosis: these patients have accelerated bone loss and an increased incidence of vertebral fractures. In contrast to glucocorticoid action, the effects of aldosterone on bone are less well understood. Recent data, demonstrating a concomitant co-secretion of glucocorticoid metabolites in patients with primary aldosteronism, could explain some of the metabolic abnormalities seen in patients with aldosterone hypersecretion. In clinical practice, patients with unexplained osteoporosis, particularly when associated with other features such as impaired glucose tolerance or hypertension, should be investigated for the possible presence of autonomous cortisol or aldosterone secretion due to an adrenal adenoma. Randomized intervention studies are needed, however, to investigate the optimum interventions for osteoporosis and other co-morbidities in these patients.

The role of steroid metabolome analysis for the diagnosis and follow-up of adrenocortical tumors.

The diagnostic work-up of adrenal tumors, often incidentally discovered, has emerged as an ever-increasing diagnostic problem for clinical endocrinologists. No imaging modality has sufficiently high sensitivity and specificity at differentiating benign from malignant adrenal lesions. It has long been observed that adrenocortical carcinomas (ACCs) present an immature pattern of steroidogenesis, dominated by steroid hormone precursors. Modern mass spectrometry-based assays can generate multi-steroid metabolite profiles in urine collections, which can detect differences between ACCs and benign adrenocortical adenomas (ACAs). This review summarizes the promising results of studies which have applied steroid metabolite profiling in biological fluids as a novel diagnostic tool for patients with adrenal tumors, as well as the challenges and limitations of this approach. It also discusses the potential role of steroid profiling as a biochemical surveillance tool to detect recurrence in patients who have undergone resection of an ACC.