Adrenocortical Lesions Research Articles

Can MDCT Enhancement Patterns Be Helpful in Differentiating Secretory from Non-Functional Adrenal Adenoma?

Background and Objectives: Primary adrenal tumors (AT) are a heterogeneous group of neoplasms due to their functional heterogeneity, which results in the diverse clinical presentation of these tumors. The purpose of this study was to examine cross-sectional imaging characteristics using multi-detector computed tomography (MDCT) to provide insight into the lesion characterization and functional status of these tumors. The radionuclide imaging using Technetium-99m radiolabeled hydrazinonicotinylacid-d-phenylalanyl1-tyrosine3-octreotide (99mTc-HYNIC-TOC), was also used in the diagnostic evaluation of these tumors. Materials and Methods: This cross-sectional study included 50 patients with confirmed diagnoses of AT (21 hormone-secreting and 29 non-functional) at the University Clinical Center, Kragujevac, Serbia, during the 2019-2022 year period. The morphological and dynamic characteristics using MDCT were performed, using qualitative, semi-quantitative, and quantitative analysis. Absolute washout (APW) and relative washout (RPW) values were also calculated. A semi-quantitative analysis of all visual findings with 99mTc-HYNIC-TOC was performed to compare the tumor to non-tumor tracer uptake. Results: A statistically significant difference was found in the MDCT values in the native phase (p < 0.05), the venous phase (p < 0.05), and the delayed phase (p < 0.001) to detect the existence of adrenal tumors. Most of these functional adrenocortical lesions (n = 44) can be differentiated using the delayed phase (p < 0.05), absolute percentage washout (APW) (p < 0.05), and relative percentage washout (RPW) (p < 0.001). Furthermore, 99mTc-HYNIC-TOC could have a high diagnostic yield to detect adrenal tumor existence (p < 0.001). There is a positive correlation between radionuclide imaging scan and APW to detect all AT (p < 0.01) and adrenocortical adenomas as well (p < 0.01). Conclusions: The results can be very helpful in a diagnostic algorithm to quickly and precisely diagnose the expansive processes of the adrenal glands, as well as to learn about the advantages and limitations of the mentioned imaging modalities.

Primary bilateral macronodular adrenal hyperplasia: clinical and laboratory features

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is characterized by bilateral benign adrenocortical lesions, which in some cases lead to Cushing syndrome (CS). Due to the low detection, non-specific, erased clinical picture and slow, long-term progression, it is difficult to assess the true prevalence of PBMAH. This also leads to fairly limited literature data. A detailed analysis of biochemical, imaging parameters, the clinical presentations, in particular, an assessment of the course of comorbidities (arterial hypertension (AH), diabetes (DM), osteoporosis), is necessary to develop an algorithm for managing patients with PBMAH. Analysis of clinical and laboratory characteristics of patients with various forms of PBMAH. A single-center, retrospective, observational, cross-sectional study was carried out. This study included 110 patients with PBMAH who got referred to the National Research Center for Endocrinology in the period from 2013-2023. We carried out comparative and correlation analysis of hormonal (plasma cortisol concentrations after 1 mg dexamethasone (1-mg DST), urinary free cortisol (СКМ), ACTH), biochemical (glycated hemoglobin), radiological data (nodular tissue volume), course of comorbidities (metabolic syndrome, DM, AH, osteoporosis) in three groups of patients: with overt CS, mild autonomous cortisol excess (MACE) and comorbid diseases, and patients with PBMAH without hormonal activity. Among 110 patients 79.1% were women, median age - 60 [51; 68]. The proportion of hormonally inactive forms of PBMAH was 37.3%, the overt CS and MACE was detected in 25.4 and 37.3% consequently. According to the hormonal -examination data: the cortisol level during 1-mg DST was 173.8 nmol/l [86.0; 441.0], ACTH - 3.35 pg/ml [1.00; 8.00], СКМ - 445.5 [249.0; 900.0]. Statistically significant positive moderate correlations were found between the volume of nodular tissue and the level of cortisol after PDT1 (r=0.40, p&lt;0.001), СКМ (r=0.29, p&lt;0.004), as well as a negative moderate correlation between the volume and the level of ACTH (r=-0.40, p&lt;0.001). When analyzing the prevalence and clinical severity of comorbid conditions, DM was diagnosed in 22 (53.7%), AH in 36 (87.8%), obesity and osteoporosis - 23 (56%) and 3 (7.3%) patients. There was no statistically significant difference in the prevalence of CS-associated diseases among the above groups (p=0.56). PBMAH is a heterogeneous pathology with different clinical, hormonal, and imaging characteristics. A correlation was found between the volume of nodular tissue and the degree of hormonal activity of PBMAH. The obtained results emphasize the difficulty in determining clear indications for surgical treatment in the group of patients with MACE. The radicality of proposed surgical procedure should be weighed against its potential complications.

A Case of ACTH Independent Macronodular Adrenocortical Hyperplasia Presenting with Conns Syndrome

Backgound: ACTH Independent macronodular adrenocortical hyperplasia (AIMAH)is a rare cause of hyperaldosteronism and is characterised by bilateral adrenal hyperplasia . One of the most common presenting symptoms is refractory hypertension. Clinical features and hypertension usually resolve following adrenalectomy. Timely diagnosis of such conditions are pertinent as they are completely treatable and thus prevents further comorbidities associated with hypertension and hypokalemia like arrhythmia.&#x0D; Case Presentation: A 57 year old male patient presented with unresolved hypertension since 15 years even after treatment with three different antihypertensives drugs since last one year. He was detected with raised serum aldosterone levels. Adrenal venous sampling showed lateralisation to the left adrenal. CT abdomen and pelvis revealed enlarged and nodular left adrenal gland and a bulky right adrenal gland. Laparoscopic left adrenalectomy was performed. Grossly left adrenal showed multiple well circumscribed yellow coloured nodules restricted to the cortex. Microscopy showed multiple well circumscribed unencapsulated nodules comprising of compact cells with clear to vacuolated cytoplasm and round central nucleus along with few foci of myelometaplasia.&#x0D; Conclusion: Conns syndrome causes a high rate of mortality and morbidity of left untreated. Serum aldosterone, serum cortisol and serum electrolyte levels should be carried out in every case of refractory hypertension to rule out adrenocortical lesions. Timely diagnosis goes a long way in reducing morbidities associated with hypertension and dyselectrolytemia.

An exception to the rule: transformation of an adrenocortical lesion with benign radiological characteristics

An exception to the rule: transformation of an adrenocortical lesion with benign radiological characteristics

Functional Characterization of Adrenocortical Masses in Nononcologic Patients Using 68Ga-Pentixafor.

We aimed to investigate the diagnostic and prognostic value of 68Ga-pentixafor PET/CT imaging in noncancer patients with suspected adrenal masses. Methods: Sixty-four patients who had benign adrenal masses on CT were retrospectively included in our study. All patients underwent 68Ga-pentixafor PET/CT, and 56 of these patients subsequently underwent adrenalectomy. The subtypes of 81 adrenal tumors, including 14 nonfunctioning adrenal nodules, 4 cortisol-producing adenomas, 41 aldosterone-producing adenomas, 5 cases of suspected unilateral adrenal hyperplasia, 15 cases of idiopathic aldosterone hyperplasia, and 2 pheochromocytomas, were determined by histology or follow-up evaluations. The diagnostic efficiency of functional lateralization was calculated by visual analysis. Semiquantitative parameters of these lesions, including SUVmax, the ratio of lesional SUVmax to normal liver SUVmean (LLR), and the ratio of lesional SUVmax to contralateral adrenal tissue SUVmean (LCR), were also calculated. Dynamic analysis was also performed on 15 patients. In addition, clinical outcomes were assessed and compared in patients who underwent adrenalectomy. Results: The sensitivity and specificity of 68Ga-pentixafor PET for functional lateralization in patients with adrenocortical lesions were 97.8% (45/46) and 87.5% (14/16), respectively. The 2 pheochromocytoma lesions had lower pentixafor uptake than the normal adrenal glands. Functioning (active) adrenocortical adenomas showed an elevated SUVmax of 16.3 ± 7.9, in comparison to 4.4 ± 1.7 in nonfunctioning (inactive) adenomas and 5.5 ± 2.7 in hyperplasia lesions (P < 0.0001). To identify active adrenocortical adenomas, a cutoff of 7.1 for SUVmax showed a sensitivity of 90.9% and a specificity of 85.3% (area under receiver-operating-characteristic curve, 0.96; P < 0.0001); a cutoff of 2.5 for LLR showed a sensitivity of 95.5% and a specificity of 88.2% (area under receiver-operating-characteristic curve, 0.97; P < 0.0001); and a cutoff of 2.4 for LCR showed a sensitivity of 88.6% and a specificity of 91.8% (area under receiver-operating-characteristic curve, 0.95; P < 0.0001). The graphical influx rate constant of active adrenocortical adenomas was significantly higher than that of inactive adenomas. Uptake values for 68Ga-pentixafor were significantly higher in patients with preferable outcomes (cured/improved) (SUVmax, 15.5 ± 8.0; LLR, 6.5 ± 4.3; LCR, 6.2 ± 5.0) than in patients with nonpreferable outcomes (no improvement) (SUVmax, 4.2 ± 0.5; LLR, 1.3 ± 0.2; LCR, 1.5 ± 0.6; all P < 0.0001). Conclusion:68Ga-pentixafor PET/CT imaging exhibits great potential for noninvasive functional lateralization and characterization in patients with adrenocortical masses.

Insulin-like growth factor 2 (IGF2) expression in adrenocortical disease due to PRKAR1A mutations compared to other benign adrenal tumors.

Insulin-like growth factor-II (IGF2), a key regulator of cell growth and development, is tightly regulated in its expression by epigenetic control that maintains its monoallelic expression in most tissues. Biallelic expression of IGF2 resulting from loss of imprinting (LOI) has been reported in adrenocortical tumors. In this study, we wanted to check whether adrenocortical lesions due to PRKAR1A mutations lead to increased IGF2 expression from LOI and compare these findings to those in other benign adrenal lesions. We compared the expression of IGF2 by RNA and protein studies in primary pigmented nodular adrenocortical disease (PPNAD) caused by PRKAR1A gene mutations to that in primary macronodular adrenocortical hyperplasia (PMAH) and cortisol-producing adenomas (CPA) that did not have any mutations in known genes. We also checked LOI in all lesions by DNA allelic studies and the expression of other components of IGF2 signaling at the RNA and protein level. We identified cell clusters overexpressing IGF2 in PPNAD; although immunostaining was patchy, overall, by RNA and immunoblotting PPNAD expressed high IGF2 message and protein. However, this was not due to LOI, as there was no correlation between IGF2 expression and the presence of LOI. Our data pointed to over-expression of IGF2 protein in PPNAD compared to other benign adrenocortical lesions, such as PMAH and CPA. However, there was no correlation of IGF2 mRNA levels with LOI of IGF2/H19. The discrepancy between mRNA and protein levels with regards to LOI points, perhaps, to different control of IGF2 gene expression in PPNAD.

Is there a role for the IGF system and epidermal growth factor (EGF) in the pathogenesis of adrenocortical adenomas? A preliminary case-control study.

Adrenal incidentalomas (AI) are very common and mostly they are non-functioning adenomas (NFA). NFAs are often associated with insulin resistance and metabolic syndrome. Several biomarkers, including certain growth factors, may participatein the pathogenesis ofmetabolic changes in patients with adrenal adenomas.Patients with NFA and age-matched control subjects were enrolled in the study. Data on age, gender, presence of metabolic syndrome or its components were obtained for each subject. Blood samples were obtained and glycemia, insulinemia, lipid profile, and selected growth factor levels were measured. Forty-three patients with NFA and 40 controls were included in the study. Differences were not found in the metabolic syndrome and its components prevalence or in the biochemical profile between patients and the control group. Significant differences were noticed in the levels of IGF1, IGF2, and IGFBP3 (p=0.016, p=0.005, p=0.004, respectively), but there were no differences in VEGF or EGF concentrations. In NFA patients, an association between glycemia and EGF levels was present (p=0.026). No significant correlations between tumor size and insulin or growth factor concentrations were present in AI patients. Significantly higher serum IGF1, IGF2, and IGFBP3 concentrations in NFA patients may support the role of the IGF axis in the pathogenesis of adrenocortical lesions.No correlation between IGFs or IGFBP3 and parameters of glucose or lipid metabolism was found. Present results may support the role of the growth hormone axis rather than hyperinsulinemia and insulin resistance in the pathogenesis of adrenocortical adenomas.

Cardiac Myxoma Caused by Fumarate Hydratase Gene Deletion in Patient With Cortisol-Secreting Adrenocortical Adenoma

Germline mutations in fumarate hydratase (FH) gene are known to cause hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and are occasionally accompanied with cutaneous and uterine leiomyoma or cortisol-producing adrenocortical hyperplasia. However, the association between FH mutations and cardiac or adrenocortical tumors has remained unknown. Here, we identified a novel deletion in FH, exhibiting cardiac myxoma and subclinical Cushing syndrome due to adrenocortical tumor. A 44-year-old man was referred to our hospital for cardiac and adrenal tumor evaluation. He had a history of multiple painful, dermal papules and nodules diagnosed as cutaneous leiomyoma. The surgically resected cardiac tumor was diagnosed as myxoma. The adrenal tumor was clinically diagnosed as subclinical Cushing syndrome. Laparoscopically resected adrenal tumor was pathologically diagnosed as adrenocortical adenoma harboring unique histological findings similar to primary pigmented nodular adrenocortical disease (PPNAD). DNA analysis revealed a germline deletion in FH c0.737delT (p. Phe225Leufs*31) and loss of heterozygosity (LOH) in cardiac myxoma. As a functional analysis of FH in cardiac myxoma, low FH protein expression with elevated 2-succinocysteine (2SC), a marker of FH dysfunction, was immunohistochemically detected. However, in adrenocortical tumor, LOH of FH was not detected, and FH or 2SC expression was not altered. This is the first case of HLRCC complicated by cardiac myxoma. LOH of FH deletion and its dysfunction were identified in cardiac myxoma. The association between FH deletion and adrenocortical lesion, however, needs to be further clarified.

SAT-068 A Precise Prevalence Of Genotypes And Histological Subtypes Of Consecutive JapanesePA CasesUndergoing Surgery From 2012 To 2017

Recent advances of molecular analysis and the development of specific monoclonal antibody against aldosterone synthase (CYP11B2) have indeed established the histological subtypes based on the localization of aldosterone overexcess and revealed the association between genotype and clinicopathological phenotype. In particular, several kinds of aldosterone-driver gene somatic mutation have been reported, including KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1. Among them, KCNJ5 somatic mutation was most frequently detected in aldosterone-producing adenoma although the prevalence of PA genotypes was markedly different among ethnic groups. The precise prevalence of genotype and histological subtypes in Japanese PA patients in large cohort has virtually remained unknown. Therefore, in this study, consecutive 125 unilateral PA cases entirely composed of Japanese patients who underwent surgery from 2012 to 2017 were histologically and genetically evaluated in order to clarify the precise prevalence of genotypes and histological subtypes among Japanese PA patients. 125 cases were precisely classified as follows based on detailed histopathological examination; single APA (84.0%), multiple (more than two) APAs (1.6%), APA + NFA (non-functional adenoma) (5.6%), MN (multiple adrenocortical micronodules) (5.6%), MN+NFA (2.4%) and DH (diffuse hyperplasia of the zona glomerulosa) (0.8%). Adrenal glands harboring single APA were further examined for genotyping. Among them, 67% harbored KCNJ5 mutated (G151R: 39.6%, L168R: 26.4%, T158A: 1.1%) and 33% harbored wild type. 5.4% of single APA clinically combined with Subclinical Cushing's syndrome, all harbored KCNJ5 mutated APAs. The results of our large-scaled analysis did firstly reveal the precise prevalence of histological subtypes and genotypes among Japanese PA patients who underwent surgery. Approximately 10% of unilateral resected PA cases histologically harbored non-neoplastic subtypes such as MN and DH. In addition to those non-neoplatic subtypes, 15% of unilateral resected PA cases other than single APA definitely required CYP11B2 immunohistochemistry in order to precisely detect the responsible lesions for aldosterone overexcess, distinguishing from the non-functional adrenocortical lesions or/and detecting more than two responsible lesions.

Concurrent pituitary and adrenocortical lesions on computed tomography imaging in dogs with spontaneous hypercortisolism

BackgroundSpontaneous hypercortisolism or Cushing's syndrome in dogs is either pituitary or adrenal dependent, but concurrent pituitary and adrenal hypercortisolism also has been reported.ObjectiveTo determine how often concurrent pituitary and adrenal lesions are present in dogs with spontaneous hypercortisolism.AnimalsTwo hundred one client‐owned dogs with spontaneous hypercortisolism.MethodsRetrospective study. Pre‐ and post‐contrast computed tomography (CT) scans of the pituitary and adrenal glands were performed in dogs with confirmed hypercortisolism.ResultsIn dogs with dexamethasone‐suppressible hypercortisolism (122/201), 78 dogs (64%) had an enlarged pituitary gland (median pituitary height/brain area [P/B], 0.43 × 10−2 mm−1; range, 0.32‐1.21 × 10−2 mm−1). Two of these 78 dogs had concurrent adrenal lesions. In the remaining dogs (44/122; 36%), the pituitary gland was not enlarged. In the dexamethasone‐resistant group (79/201), the pituitary gland was enlarged in 47 dogs (59%; median P/B, 0.57 × 10−2; range, 0.32‐1.50 × 10−2 mm−1). Eight of these 47 dogs (17%) had concurrent adrenal lesions. In the remaining 32 dexamethasone‐resistant dogs (41%), the pituitary gland was not enlarged. Among them, 27 dogs had adrenal lesions and suppressed ACTH concentrations consistent with adrenal‐dependent hypercortisolism and 5 dogs were diagnosed with pituitary‐dependent hypercortisolism.Conclusions and Clinical ImportanceConcurrent pituitary and adrenal lesions were present in 5% of all dogs with hypercortisolism and in 10% of the dexamethasone‐resistant dogs. Diagnostic imaging of both pituitary and adrenal glands should be included in the diagnostic evaluation of every dog with spontaneous hypercortisolism to obtain information needed for estimation of prognosis and choosing the optimal treatment.

Development of [18F]FAMTO: A novel fluorine-18 labelled positron emission tomography (PET) radiotracer for imaging CYP11B1 and CYP11B2 enzymes in adrenal glands

IntroductionPrimary aldosteronism accounts for 6–15% of hypertension cases, the single biggest contributor to global morbidity and mortality. Whilst ~50% of these patients have unilateral aldosterone-producing adenomas, only a minority of these have curative surgery as the current diagnosis of unilateral disease is poor. Carbon-11 radiolabelled metomidate ([11C]MTO) is a positron emission tomography (PET) radiotracer able to selectively identify CYP11B1/2 expressing adrenocortical lesions of the adrenal gland. However, the use of [11C]MTO is limited to PET centres equipped with on-site cyclotrons due to its short half-life of 20.4 min. Radiolabelling a fluorometomidate derivative with fluorine-18 (radioactive half life 109.8 min) in the para-aromatic position ([18F]FAMTO) has the potential to overcome this disadvantage and allow it to be transported to non-cyclotron-based imaging centres. MethodsTwo strategies for the one-step radio-synthesis of [18F]FAMTO were developed. [18F]FAMTO was obtained via radiofluorination via use of sulfonium salt (1) and boronic ester (2) precursors. [18F]FAMTO was evaluated in vitro by autoradiography of pig adrenal tissues and in vivo by determining its biodistribution in rodents. Rat plasma and urine were analysed to determine [18F]FAMTO metabolites. Results[18F]FAMTO is obtained from sulfonium salt (1) and boronic ester (2) precursors in 7% and 32% non-isolated radiochemical yield (RCY), respectively. Formulated [18F]FAMTO was obtained with >99% radiochemical and enantiomeric purity with a synthesis time of 140 min from the trapping of [18F]fluoride ion on an anion-exchange resin (QMA cartridge). In vitro autoradiography of [18F]FAMTO demonstrated exquisite specific binding in CYP11B-rich pig adrenal glands. In vivo [18F]FAMTO rapidly accumulates in adrenal glands. Liver uptake was about 34% of that in the adrenals and all other organs were <12% of the adrenal uptake at 60 min post-injection. Metabolite analysis showed 13% unchanged [18F]FAMTO in blood at 10 min post-administration and rapid urinary excretion. In vitro assays in human blood showed a free fraction of 37.5%. Conclusions[18F]FAMTO, a new 18F-labelled analogue of metomidate, was successfully synthesised. In vitro and in vivo characterization demonstrated high selectivity towards aldosterone-producing enzymes (CYP11B1 and CYP11B2), supporting the potential of this radiotracer for human investigation.

Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing's syndrome

Background GIP-dependent Cushing's syndrome is caused by ectopic expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in cortisol-producing adrenal adenomas or in bilateral macronodular adrenal hyperplasias. Molecular mechanisms leading to ectopic GIPR expression in adrenal tissue are not known. Methods We performed molecular analyses on 14 adrenal samples obtained from 12 patients with overt GIP-dependent Cushing's syndrome and from one patient with GIP-dependent aldosteronism. Results Nascent RNA FISH showed that GIPR expression in all adenoma and hyperplasia samples occurred through transcriptional activation of a single allele of the GIPR gene. While no abnormality was detected in proximal GIPR promoter methylation, we identified by CGH-array somatic duplications in chromosome region 19q13.32 containing the GIPR locus in the adrenocortical lesions derived from 3 patients. In 2 adenoma samples, the duplicated 19q13.32 region was rearranged with other chromosome regions, whereas a single tissue sample with hyperplasia had 19q duplication only. These duplications were further confirmed by DNA FISH. Among the 5 genes encompassed in the smallest region of overlap, only GIPR was over expressed. We demonstrated in vitro that juxtaposition with cis-acting regulatory sequences such as glucocorticoid response elements in the newly identified genomic environment drives abnormal expression of the translocated GIPR allele in HEK293 T and H295R cells. Conclusion Altogether, our results provide insight into the molecular pathogenesis of GIP-dependent Cushing's syndrome, occurring through monoallelic transcriptional activation of GIPR driven in some adrenal lesions by structural variations.

The computed tomography adrenal wash-out analysis properly classifies cortisol secreting adrenocortical adenomas.

Adrenocortical lesions are characterized through imaging, hormonal and histopathological analysis. Our aim was to compare the radiological features of adrenocortical lesions with their cortisol-secreting status and histopathological Weiss score. Seventy five patients operated between 2004 and 2016 in the University Hospital of Nancy for either adrenocortical carcinomas (ACC) or adrenocortical adenomas (ACA) were enrolled in this study. We collected cortisol parameters, Computed Tomography (CT) scans (unenhanced density, wash-out (WO) analysis) and 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) datas. The histopathological Weiss score ultimately differentiates ACA (score ≤ 2) from ACC (score ≥ 3). One-way ANOVA, Fisher's exact and unpaired t tests were used for statistical analysis with significancy reached at p < 0.05. There were 23 ACC and 52 ACA with 40 patients (53%) who had an autonomous secretion of cortisol. On CT scan, ACC were larger compared to ACA (108 vs. 37 mm, p < 0.0001). A roughly similar proportion of cortisol-secreting (22/25) and non-secreting (15/19) ACA were atypical (i.e., unenhanced density value ≥ 10 Hounsfield Units [HU]), however 85% of cortisol-secreting vs. 40% of non-secreting ACA were classified as benigns by the relative WO analysis (p = 0.08). Likewise, there was a trend for a higher 18F-FDG uptake in cortisol-secreting ACA compared to non-secreting ACA (p = 0.053). The relative adrenal WO analysis consolidates the benign nature of an ACA, especially in case of cortisol oversecretion, a condition known to compromise the diagnostic accuracy of the 10 HU unenhanced CT attenuation threshold.

Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing's syndrome.

GIP-dependent Cushing's syndrome is caused by ectopic expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in cortisol-producing adrenal adenomas or in bilateral macronodular adrenal hyperplasias. Molecular mechanisms leading to ectopic GIPR expression in adrenal tissue are not known. Here we performed molecular analyses on adrenocortical adenomas and bilateral macronodular adrenal hyperplasias obtained from 14 patients with GIP-dependent adrenal Cushing's syndrome and one patient with GIP-dependent aldosteronism. GIPR expression in all adenoma and hyperplasia samples occurred through transcriptional activation of a single allele of the GIPR gene. While no abnormality was detected in proximal GIPR promoter methylation, we identified somatic duplications in chromosome region 19q13.32 containing the GIPR locus in the adrenocortical lesions derived from 3 patients. In 2 adenoma samples, the duplicated 19q13.32 region was rearranged with other chromosome regions, whereas a single tissue sample with hyperplasia had a 19q duplication only. We demonstrated that juxtaposition with cis-acting regulatory sequences such as glucocorticoid response elements in the newly identified genomic environment drives abnormal expression of the translocated GIPR allele in adenoma cells. Altogether, our results provide insight into the molecular pathogenesis of GIP-dependent Cushing's syndrome, occurring through monoallelic transcriptional activation of GIPR driven in some adrenal lesions by structural variations.

Analysis of histological and immunohistochemical patterns of benign and malignant adrenocortical tumors by computerized morphometry

Diagnosis of benign and purely localized malignant adrenocortical lesions is still a complex issue. Moreover, histology-based diagnosis may suffer of a moment of subjectivity due to inter- and intra-individual variations. The aim of the present study was to assess, by computerized morphometry, the morphological features in benign and malignant adrenocortical neoplasms.Eleven adrenocortical adenomas (ACA) were compared with 18 adrenocortical cancers (ACC). All specimens were stained with H&E, cellular proliferation marker Ki-67 and reticulin. We generated a morphometric model based on the analysis of volume fractions occupied by Ki-67 positive and negative cells (nuclei and cytoplasm), vascular and inflammatory compartment; we also analyzed the surface fraction occupied by reticulin. We compared the quantitative data of Ki-67 obtained by morphometry with the quantification resulting from pathologist’s visual reading.The volume fraction of Ki-67 positive cells in ACCs was higher than in ACAs. The volume fraction of nuclei in unit volume and the nuclear/cytoplasmic ratio in both Ki-67 negative cells and Ki-67 positive cells were prominent in ACCs. The surface fraction of reticulin was considerably lower in ACCs.Our computerized morphometric model is simple, reproducible and can be used by the pathologist in the histological workup of adrenocortical tumors to achieve precise and reader-independent quantification of several morphological characteristics of adrenocortical tumors.

PRKACA: the catalytic subunit of protein kinase A and adrenocortical tumors.

Cyclic-AMP (cAMP)-dependent protein kinase (PKA) is the main effector of cAMP signaling in all tissues. Inactivating mutations of the PRKAR1A gene, coding for the type 1A regulatory subunit of PKA, are responsible for Carney complex and primary pigmented nodular adrenocortical disease (PPNAD). PRKAR1A inactivation and PKA dysregulation have been implicated in various types of adrenocortical pathologies associated with ACTH-independent Cushing syndrome (AICS) from PPNAD to adrenocortical adenomas and cancer, and other forms of bilateral adrenocortical hyperplasias (BAH). More recently, mutations of PRKACA, the gene coding for the catalytic subunit C alpha (Cα), were also identified in the pathogenesis of adrenocortical tumors. PRKACA copy number gain was found in the germline of several patients with cortisol-producing BAH, whereas the somatic Leu206Arg (c.617A>C) recurrent PRKACA mutation was found in as many as half of all adrenocortical adenomas associated with AICS. In vitro analysis demonstrated that this mutation led to constitutive Cα activity, unregulated by its main partners, the PKA regulatory subunits. In this review, we summarize the current understanding of the involvement of PRKACA in adrenocortical tumorigenesis, and our understanding of PKA's role in adrenocortical lesions. We also discuss potential therapeutic advances that can be made through targeting of PRKACA and the PKA pathway.

Pediatric adrenocortical neoplasms: can imaging reliably discriminate adenomas from carcinomas?

There is a paucity of literature describing and comparing the imaging features of adrenocortical adenomas and carcinomas in children and adolescents. To document the CT and MRI features of adrenocortical neoplasms in a pediatric population and to determine whether imaging findings (other than metastatic disease) can distinguish adenomas from carcinomas. We searched institutional medical records to identify pediatric patients with adrenocortical neoplasms. Pre-treatment CT and MRI examinations were reviewed by two radiologists in consensus, and pertinent imaging findings were documented. We also recorded relevant histopathological, demographic, clinical follow-up and survival data. We used the Student's t-test and Wilcoxon rank sum test to compare parametric and nonparametric continuous data, and the Fisher exact test to compare proportions. We used receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic performances of tumor diameter and volume for discriminating carcinoma from adenoma. A P-value ≤0.05 was considered statistically significant. Among the adrenocortical lesions, 9 were adenomas, 15 were carcinomas, and 1 was of uncertain malignant potential. There were no differences in mean age, gender or sidedness between adenomas and carcinomas. Carcinomas were significantly larger than adenomas based on mean estimated volume (581ml, range 16-2,101 vs. 54ml, range 3-197ml; P-value = 0.003; ROC area under the curve = 0.92) and mean maximum transverse plane diameter (9.9cm, range 3.0-14.9 vs. 4.4cm, range 1.9-8.2cm; P-value = 0.0001; ROC area under the curve = 0.92). Carcinomas also were more heterogeneous than adenomas on post-contrast imaging (13/14 vs. 2/9; odds ratio [OR] = 45.5; P-value = 0.001). Six of 13 carcinomas and 1 of 8 adenomas contained calcification at CT (OR = 6.0; P-value = 0.17). Seven of 15 children with carcinomas exhibited metastatic disease at diagnosis, and three had inferior vena cava invasion. Median survival for carcinomas was 27months. In our experience, pediatric adrenocortical carcinomas are larger, more heterogeneous, and more often calcified than adenomas, although there is overlap in their imaging appearances.

Adrenal lipoadenoma

Introduction Presence of mature adipose tissue, lymphoid infiltration, and bone marrow cells is a rare but well-known occurrence in the adrenal cortex and in both hyperplastic and neoplastic adrenocortical lesions. The present report describes a case of adrenocortical adenoma with a large component of fatty tissue lacking hematopoietic component.

123I]Iodometomidate Imaging in Adrenocortical Carcinoma

Imaging with [¹²³I]iodometomidate ([¹²³I]IMTO) has been shown to diagnose adrenocortical lesions with high sensitivity and specificity. Our objective was to evaluate the clinical utility of [¹²³I]IMTO imaging in adrenocortical carcinoma (ACC). We conducted a prospective monocentric diagnostic study and a prospective case series at a single tertiary referral center. Fifty-eight patients with histologically confirmed ACC, all European Network for the Study of Adrenal Tumors stage IV (with distant metastases), received 185 MBq [¹²³I]IMTO. Sequential planar whole-body scans until 24 hours post injection and single photon emission computed tomography/computed tomography (SPECT/CT) hybrid imaging 4 to 6 hours post injection were performed. Outcome measures included uptake of [¹²³I]IMTO in ACC lesions, sensitivity and specificity of [¹²³I]IMTO imaging compared with conventional imaging, and number of patients eligible for [¹³¹I]IMTO therapy. Of 430 lesions detected by conventional imaging, 30% showed strong, 8% moderate, and 62% no tracer accumulation. [¹²³I]IMTO detected both primary and metastatic lesions of ACC. However, a substantial percentage of lesions failed to show [¹²³I]IMTO uptake. The overall sensitivity and specificity values were 38% and 100%, respectively. Thirty-four patients (59%) had at least 1 [¹²³I]IMTO-positive lesion. Cortisol and aldosterone secretion by ACC was positively correlated to [¹²³I]IMTO uptake (P = .01); cytotoxic chemotherapy and mitotane treatment presumably did not influence tracer uptake. Twenty-one patients (36.2%) had radiotracer uptake in all lesions ≥ 2 cm and therefore were potential candidates for targeted systemic radiotherapy with [¹³¹I]IMTO. About one-third of patients with ACC show specific retention of [¹²³I]IMTO in metastatic lesions. This study provides support for the conduct of a prospective trial to determine whether the first molecular informed therapy using [¹³¹I]IMTO will be of value to patients with metastatic ACC.

123I]Iodometomidate imaging in adrenocortical carcinoma

Context: Imaging with [123I]iodometomidate ([123I]IMTO) has been shown to diagnose adrenocortical lesions with high sensitivity and specificity.