Ectopic adrenal tissue in the kidney: A systematic review

Introduction: Ectopic adrenal tissue in the kidney, including “Ectopic adrenal tissue” and “Adrenal-renal fusion”, is a rare event with a specific behavior which may be difficult to distinguish clinically from renal neoplasms. We performed a systematic review on ectopic adrenal tissue variants reported in the literature underlining its clinical aspects. Methods: Manuscripts which presented a case report or case series of ectopic adrenal tissue in the kidney were included even if published in original articles, reviews, or letters to the editor. A specific search on SCOPUS®, PubMed®, and Web of Science® database was performed. Only English language papers published in a period ranging between August 1991 and April 2020 were considered. Additionally, a case we had at our institution is described, and its characteristics are included. Data on clinical presentation, type of adrenal anomaly, location, anatomopathological and immune-histotype characteristics were collected. Results: We identified 888 manuscripts. Among these 29 were included in this systematic review. Overall, 39 patients with renal adrenal fusion or adrenal ectopia were considered. In most cases, the diagnosis was made incidentally, or following investigation for flank pain, abdominal pain, or endocrinological disorders. CT scan frequently identified a solid vascularized lesion that was difficult to distinguish from renal neoplasm. Adrenal fusion was mostly located at the level of the upper pole. Adrenal rest was found in the renal parenchyma, renal hilum, or retroperitoneum in close proximity to the renal peduncle. Often these ectopic adrenal tissue lesions follow a benign behavior and can be classified as functioning or non-functioning adenomas. Rarely, they may experience neoplastic degeneration. The most frequently positive markers were inhibin, vimentin, melan-A, synaptophysin and anti-p450 scc. Conclusions: Ectopic adrenal tissue in the kidney is a rare event with specific clinical characteristics that need to be identified in order to arrive at a correct diagnosis and carry out appropriate treatment management.

Therapeutic Effect of Curcumin on Scanning Electron Microscopy of Rat Adrenal Gland in Experimental Fluorosis

Aim: The present study was designed to investigate the therapeutic role of Curcumin against fluoride induced toxicity on adrenal gland of rats by using scanning electron microscopy (SEM). Methodology: Wistar albino rats were divided randomly into six groups The group I was administered with 1 ml of deionized water/kg b.w./day orally for 40 days. The Groups II and III were given 300 and 600 mg of NaF/kg b.w./day for the same period, respectively. The group IV was given 200 mg/kg b.w. of Curcumin for 20 days. The Groups V and VI were treated with 300 and 600 mg of NaF/kg b.w./day for 40 days respectively were post-treated with 200 mg of Curcumin for next 20 days. The animals were excised and adrenal tissue was taken out and processed for SEM. Results: The results revealed that rats exposed to 300 mg/kg b.w./day of NaF showed rough edges, numerous microvilli and damaged surface with crystal depositions. Also, numerous granules were distributed all over the surface. The rats treated with 600 mg/kg b.w./day of NaF showed decellularized adrenal tissue along with network of collagen fibres. Moreover, adrenal gland surface displayed abrasions and distorted cuboidal cells. The filopodia were prominent on the surface and wall of cavity possessed rough outline. After post-treatment with Curcumin, fluoridated adrenal gland of rats showed normal structure, reappearance of cuboidal cells on the surface as well as less number of microvilli and filopodia. Conclusion: The post-treatment with Curcumin possess therapeutic potential against NaF induced toxicity in adrenal gland of rats.

Can Extra Adrenal Cortisol Secretion Occur in an Adrenalectomized Patient?

Background: Established medical practice is that adrenalectomized patients require lifelong steroid replacement. We report a case which challenges that assumption. Clinical Case: A 38 year old female underwent transsphenoidal resection of a proven ACTH secreting pituitary adenoma. Post operatively her pituitary function was preserved, but due to residual tumour activity and the desire to preserve fertility, she had a bilateral adrenalectomy one year later and commenced hydrocortisone replacement. Subsequent pituitary imaging did not show recurrence of the tumour and her visual fields were stable, however her ACTH remained elevated at 100 and 130ng/L (09:00 <50 ng/L) despite steroid replacement.14 years after adrenalectomy she noticed weight gain and increased body hair. She also reported sometimes missing her hydrocortisone due to her busy job without ill effects. Her 9 am cortisol pre-hydrocortisone was elevated at 333 nmol/L (9am: 140–690 nmol/L) with ACTH of 203.0 ng/L (09:00 <50ng/L) She was able to suppress cortisol normally after a Dexamethasone suppression test. CT of her adrenals found no adrenal tissue. By now she had weaned herself off hydrocortisone, keeping an emergency supply. SST showed a cortisol of 320 nmol/L at 30 minutes, 360 nmol/L at 60 minutes with an elevated ACTH of 140 ng/L (09:00 <50 ng/L). Her weight gain and body hair growth stabilised. Discussion: We have demonstrated that this adrenalectomized patient has ACTH driven endogenous cortisol secretion which may be due to residual adrenal tissue due to seeding after surgery or the presence of steroid synthesis elsewhere. Extra adrenal sources for glucocorticoid production are known such as skin, gonads and thymus. However, the levels are insufficient to mount a significant stress response. There is evidence of adrenal regeneration in adrenalectomized animals. The regeneration is primarily of the adrenal cortex and does not involve the medulla. There has been one case report in literature of a 11 year old German boy who had adrenal regeneration detected on adrenal scintigraphy (Bilateral normal adrenal glands with normal activity) 13 years after adrenalectomy for Cushing’s disease. References: Gotlieb N, Albaz E, Shaashua L, et al. Regeneration of Functional Adrenal Tissue Following Bilateral Adrenalectomy. Endocrinology. 2018;159(1):248–259. doi:10.1210/en.2017-00505 Taves MD, Gomez-Sanchez CE, Soma KK. Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function. Am J Physiol Endocrinol Metab. 2011;301(1):E11-E24. doi:10.1152/ajpendo.00100.2011

Aldosterone-Regulating Receptors and Aldosterone-Driver Somatic Mutations

BackgroundSomatic gene mutations that facilitate inappropriate intracellular calcium entrance have been identified in most aldosterone-producing adenomas (APAs). Studies suggest that angiotensin II and adrenocorticotropic hormone (ACTH) augment aldosterone production from APAs. Little is known, however, regarding possible variations in response to hormonal stimuli between APAs with different aldosterone-driver mutations.ObjectiveTo analyze the transcript expression of type 1 angiotensin II receptors (AGTR1), ACTH receptors (MC2R), and melanocortin 2 receptor accessory protein (MRAP) in APAs with known aldosterone-driver somatic mutations.MethodsRNA was isolated from APAs with mutations in: KCNJ5 (n = 14), ATP1A1 (n = 14), CACNA1D (n = 14), and ATP2B3 (n = 5), and from normal adjacent adrenal tissue (n = 45). Transcript expression of MC2R, MRAP, AGTR1, aldosterone synthase (CYP11B2), 17α-hydroxylase/17,20-lyase (CYP17A1), and 11β-hydroxylase (CYP11B1) were quantified using quantitative RT-PCR and normalized to β-actin.ResultsCompared to adjacent normal adrenal tissue, APAs had higher transcript levels of CYP11B2 (2,216.4 [1,112.0, 2,813.5]-fold, p < 0.001), MC2R (2.88 [2.00, 4.52]-fold, p < 0.001), and AGTR1 (1.80 [1.02, 2.80]-fold, p < 0.001]), and lower transcript levels of MRAP, CYP17A1, and CYP11B1 (0.28–0.36, p < 0.001 for all). MC2R and CYP11B2 transcripts were lower in APAs with KCNJ5 vs. other mutations (p < 0.01 for both). MC2R expression correlated positively with that of AGTR1 in APAs harboring KCNJ5 and CACNA1D mutations, and with MRAP expression in APAs harboring ATPase mutations.ConclusionsWhile MC2R and AGTR1 are expressed in all APAs, differences were observed based on the underlying aldosterone-driver somatic mutations. In tandem, our findings suggest that APAs with ATPase-mutations are more responsive to ACTH than KCNJ5-mutated APAs.

Ectopic Adrenocortical Tissue Attached to the Inguinal Sac in an Adult

Inguinal localization of ectopic adrenal tissue is a rare condition in literature. We report an unusual case of a 28-year-old male patient with ectopic adrenocortical tissue, which was noticed coincidentally as a orangeyellowish nodule during surgery of inguinal hernia and resected for patological examination.

Establishment of a Novel Human Fetal Adrenal Culture Model that Supports de Novo and Manipulated Steroidogenesis

Context Disorders affecting adrenal steroidogenesis promote an imbalance in the normally tightly controlled secretion of mineralocorticoids, glucocorticoids, and androgens. This may lead to differences/disorders of sex development in the fetus, as seen in virilized girls with congenital adrenal hyperplasia (CAH). Despite the important endocrine function of human fetal adrenals, neither normal nor dysregulated adrenal steroidogenesis is understood in detail. Objective Due to significant differences in adrenal steroidogenesis between human and model species (except higher primates), we aimed to establish a human fetal adrenal model that enables examination of both de novo and manipulated adrenal steroidogenesis. Design and Setting Human adrenal tissue from 54 1st trimester fetuses were cultured ex vivo as intact tissue fragments for 7 or 14 days. Main Outcome Measures Model validation included examination of postculture tissue morphology, viability, apoptosis, and quantification of steroid hormones secreted to the culture media measured by liquid chromatography-tandem mass spectrometry. Results The culture approach maintained cell viability, preserved cell populations of all fetal adrenal zones, and recapitulated de novo adrenal steroidogenesis based on continued secretion of steroidogenic intermediates, glucocorticoids, and androgens. Adrenocorticotropic hormone and ketoconazole treatment of ex vivo cultured human fetal adrenal tissue resulted in the stimulation of steroidogenesis and inhibition of androgen secretion, respectively, demonstrating a treatment-specific response. Conclusions Together, these data indicate that ex vivo culture of human fetal adrenal tissue constitutes a novel approach to investigate local effects of pharmaceutical exposures or emerging therapeutic options targeting imbalanced steroidogenesis in adrenal disorders, including CAH.

High Prevalence of Adrenal Remnant Tissue in Patients Undergoing Bilateral Adrenalectomy for Cushing’s Disease

Bilateral adrenalectomy (BLA) is a treatment option for patients with Cushing’s Disease (CD) if transsphenoidal pituitary surgery fails or is not a therapeutic option. For most patients, BLA eliminates endogenous glucocorticoid and mineralocorticoid production, but for a small number of patients, endogenous secretion of adrenal hormones from adrenal tissue continues or recurs, leading to signs and symptoms of hypercortisolism. If adrenal tissue is confined to the adrenal bed, it is considered adrenal remnant tissue, while if it is outside the adrenal bed, it is considered adrenal rest tissue. We retrospectively evaluated morning serum cortisol, nighttime serum cortisol, nighttime salivary cortisol, and 24-h urine free cortisol on at least three occasions in 10 patients suspected of having endogenous cortisol production. Imaging of adrenal remnant tissue was also reviewed. Ten of 51 patients who underwent BLA during this time period had adrenal remnant/rest tissue marked by detectable endogenous glucocorticoid production; 9 of the 10 patients had signs and symptoms of hypercortisolism. Localization and treatment proved difficult. We conclude that the incidence of adrenal remnant/rest tissue in those undergoing BLA following unsuccessful pituitary surgery was 12% although there may have been a selection bias affecting this prevalence. The first indication of remnant tissue occurrence is a reduction in glucocorticoid replacement with symptoms of hypercortisolism. If this occurs, endogenous cortisol production should be tested for by cortisol measurements using a highly specific cortisol assay while the patient is taking dexamethasone or no glucocorticoid replacement. Endocrinologists need to monitor the development of both adrenal remnant tissue and Nelson’s syndrome following BLA.

OR19-01 IHC-Guided Capture of Adrenocortical Zones from Archival Formalin-Fixed, Paraffin-Embedded Adrenal Tissue Allows the Study Of RNA Expression Profiles

Introduction: Characterization of human adrenal RNA has relied on fresh tissue, or laser capture from OCT-embedded frozen tissue. These approaches have allowed identification of differences between zones of the adrenal cortex, but the need for fresh or frozen material has limited access for most researchers and has limited the number of samples that can be studied. In order to expand tissue availability and researcher access, we examined the use of archival formalin-fixed, paraffin-embedded (FFPE) adrenals for the capture and analysis of RNA from each adrenal zone. Methods: 13 normal adrenals were obtained from deceased renal donors. Following FFPE, tissue serial sections were examined for zonal histology. Immunohistochemistry (IHC) was used to guide the capture of specific adrenal zones from FFPE tissue. CYP11B2, CYP17A1, and CYB5A IHC was used to visualize the zona glomerulosa (ZG), zona fasciculata (ZF), and zona reticularis (ZR) respectively. Serial unstained sections were then dissected under a dissection microscope based on IHC-guided visualization of the ZG, ZF, and ZR. Following capture of zones and isolation of RNA, quantitative PCR (qPCR) was used to examine zonal expression of transcripts for the IHC markers. Using housekeeping genes for normalization, specific zonal markers identified successfully isolated zones. Results: Adrenals with clear zonal expression of CYP11B2 (ZG), HSD3B2 (ZG/ZF), and CYB5A (ZR) were included for study. Based on marker inclusion criteria, 3 ZG, 3 ZF, 3 ZR, and 3 medulla samples were studied. Using these samples, confirmatory markers of ZG (VSNL1), ZF (CYP17A1), ZR (SLC27A2), and medulla (TH) were analyzed by qPCR. Levels of these transcripts segregated as expected in the adrenal zones. Discussion: The use of archival normal and pathologic adrenal tissue for RNA analysis would increase the number of samples available to many research groups. Our data demonstrates the ability to capture and use FFPE tissue for the capture and analysis of RNA. Future comparison of normal adrenal zones to adrenal tumor phenotypes will improve our understanding of tumor biology and provide potential genetic markers for targeted therapeutics.