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Purpose: To describe a novel technique of transvenous radiofrequency catheter ablation of an aldosterone-producing adenoma (APA) of the left adrenal gland using the GOS System (Japan Lifeline, Tokyo, Japan). Using the GOS system, a flexible radiofrequency tip catheter can be inserted into the adrenal central and tributary veins, the drainers for functional tumors. Materials and methods: An APA at the left adrenal gland, which was diagnosed by segmental adrenal venous sampling following administration of 0.25 mg cosyntropin, was ablated using the GOS catheter inserted into adrenal tributary veins via a right femoral vein 7-Fr sheath. The effect of radiofrequency ablation on APA was assessed using the international consensus on surgical outcomes for unilateral primary aldosteronism (PA). Results: No device-related complications were observed. The patient was deeply sedated under blood pressure and heart rate control with continuous administration of β-blockers. Then, the tumor and surrounding adrenal gland were cauterized at 7000 J two times each in sequence. The output time was 7−11 min for each ablation and 80 min in total. For blood pressure and pulse rate control, esmolol hydrochloride and phentolamine mesylate were used. The contrast enhancement of APA disappeared on dynamic CT immediately after the procedure. PA was biochemically cured until 12 months after the procedure. Conclusion: Using the radiofrequency device with the GOS catheter and system is a method for cauterizing adrenal tumors from blood vessels. This approach resulted in a marked reduction in aldosterone concentrations and a complete biochemical cure of PA over the observation period. [ABSTRACT FROM AUTHOR]

Evaluation of feasibility and safety of percutaneous radiofrequency ablation using bipolar radiofrequency devices in a prospective multicenter cohort of patients with benign aldosterone-producing adenoma. A total of five institutions participated. CT-guided percutaneous RFA was performed for patients diagnosed as APA. The safety of the procedure was evaluated using the Common Terminology Criteria for Adverse Events. During the 84-day follow-up period, serial changes in plasma aldosterone concentration and plasma renin activity were measured. The percentage of patients with normalized hormonal activity after the procedure, was calculated with 95% confidence intervals. Forty patients were enrolled, and two patients were excluded for cerebral hemorrhage and no safe puncture root. In another patients, RFA was tried, but an intraprocedural intercostal arterial injury occurred. Consequently, RFA was completed in thirty-seven patients (20 men, 17 women; mean age, 50.4 ± 10.0 year). The tumor size was 14.8 ± 3.8 mm. The treatment success rate of the ablation was 94.6% (35/37), and a 2nd session was performed in 2.7% (1/37) patients. Grade 4 adverse events were observed in 4 out of 38 sessions (10.5%). The normalization of plasma aldosterone concentration or aldosterone-renin ratio was 86.5% (72.0–94.1: 95% confidence interval) on day 84. Percutaneous CT-guided RFA for APA using a bipolar radiofrequency system was safe and feasible with clinical success rate of 86.5% on day 84. [ABSTRACT FROM AUTHOR]

Purpose: The aim was to evaluate a flexible device for transvenous adrenal gland radiofrequency ablation in vitro and in an in vivo animal model. Materials and Methods: A flexible radiofrequency-tip catheter with an inner-cooling mechanism and a guidewire lumen was made. Then, using a polyvinyl alcohol gel model, the ablation diameter was evaluated and how much energy to deliver in vivo was determined. Finally, transvenous radiofrequency ablation of the left adrenal glands of two pigs was performed, delivering 5000 or 7000 J in a single dose to each. The ablation effects were also assessed by histological examination of hematoxylin–eosin-stained sections. Results: The mean ablation diameters in the gel model were 20.2 and 21.9 mm in the short axis and 15 and 20 mm in the long axis for 5000 or 7000 J, respectively. The device was inserted into porcine left adrenal vein with no complications. The mean ablation diameters were 10 mm in the shorter axis (whole thickness of porcine left adrenal gland) in the porcine model for 7000 J. Transient increases in blood pressure and heart rate occurred during ablation. Histologically, the adrenal gland showed severe necrosis at ablated area. There was venous congestion upstream in a non-ablated area, and thermal damage to surrounding organs was not observed. Conclusions: A flexible radiofrequency-tip catheter could be inserted successfully into the left adrenal vein. The left adrenal gland was entirely ablated without any thermal damage to surrounding organs. We suggest transvenous adrenal ablation has potential as a therapeutic option for primary aldosteronism. [ABSTRACT FROM AUTHOR]

In chromaffin cells, tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine β-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT) are mainly involved in catecholamine synthesis. In this study, we evaluated the association between the status of catecholamine-synthesizing enzymes and histopathological features of pheochromocytoma and extraadrenal paraganglioma with special emphasis upon their postoperative clinical behavior. Immunohistochemical evaluation of TH, DBH, AADC, PNMT, Ki 67, and S-100 was performed in 29 pheochromocytoma and 10 extraadrenal paraganglioma and one lymph node harboring metastatic pheochromocytoma. Among these cases, metastasis was subsequently developed in three cases. Urinary normetanephrine (U-NM) levels were significantly higher in clinical metastatic cases than non-metastatic ones. Ki 67 labeling index was significantly higher in both clinical metastatic cases and the Adrenal Gland Scaled Score (PASS) score of ≧ 4 cases than PASS < 4 cases, although this score was originally used in pheochromocytoma. H-score of AADC and DBH were significantly lower in PASS ≧ 4 cases than those with < 4 cases, and in the cases associated with intratumoral necrosis (n = 4), the presence of spindle shaped tumor cells (n = 4), and large nests of cells or diffuse growth (n = 5). Lower status of intratumoral AADC could be related to poor differentiation of tumor cells in both catecholamine production and morphology and could be related to aggressive biological behavior of both pheochromocytoma and extraadrenal paraganglioma. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate visualization of the right adrenal vein (RAV) with multidetector CT and non-contrast-enhanced MR imaging in patients with primary aldosteronism.Methods: A total of 125 patients (67 men) scheduled for adrenal venous sampling (AVS) were included. Dynamic 64-detector-row CT and balanced steady-state free precession-based non-contrast-enhanced 3-T MR imaging were performed. RAV visualization based on a four-point score was documented. Both anatomical location and variation on cross-sectional imaging were evaluated, and the findings were compared with catheter venography as the gold standard.Results: The RAV was visualized in 93.2% by CT and 84.8% by MR imaging (p = 0.02). Positive predictive values of RAV visualization were 100% for CT and 95.2% for MR imaging. Imaging score was significantly higher in CT than MR imaging (p < 0.01). The RAV formed a common trunk with an accessory hepatic vein in 16% of patients. The RAV orifice level on cross-sectional imaging was concordant with catheter venography within the range of 1/3 vertebral height in >70% of subjects. Success rate of AVS was 99.2%.Conclusions: Dynamic CT is a reliable way to map the RAV prior to AVS. Non-contrast-enhanced MR imaging is an alternative when there is a risk of complication from contrast media or radiation exposure.Key Points: Dynamic CT and non-contrast-enhanced MR imaging detect the right adrenal vein (RAV). Dynamic CT can visualize the RAV more than non-contrast-enhanced MR imaging. Mapping the RAV helps to achieve successful adrenal venous sampling. Sixteen per cent of RAVs share the common trunk with accessory hepatic veins. [ABSTRACT FROM AUTHOR]

The pre-B lymphocyte protein 3 (VPREB3) is expressed during B cell differentiation and in subsets of mature B lymphocytes and is mainly found in bone marrow and lymphoid tissue germinative centers. So far, its function in B cells remains to be clarified. The messenger RNA (mRNA) of VPREB3 was previously detected in aldosterone-producing adenomas (APA); however, further information about this protein in human adrenocortical cells and tissues is currently unavailable. Therefore, in the present study, we, for the first time, investigate the protein expression of VPREB3 in human adrenocortical tissues. In addition, we approach the previously suggested similarities in expression patterns of aldosterone-producing cells and Purkinje neurons. Immunohistochemical analysis of VPREB3 was performed in 13 nonpathological adrenals (NA), 6 adrenal glands with idiopathic hyperaldosteronism (IHA), 18 APA, 5 cortisol-producing adenomas (CPA), and 5 nonpathological human cerebellum specimens. The mRNA levels of VPREB3, steroidogenic enzymes, and other aldosterone biosynthesis markers were detected in 53 APA samples using real-time RT-PCR (qPCR) and compared to the clinical data of APA patients. In our results, the VPREB3 protein was diffusely detected in APA, partially or weakly detected in CPA, and immunolocalized in the zona glomerulosa of NA and IHA, as well as in the cytoplasm of cerebellar Purkinje cells. In APA, VPREB3 mRNA levels were significantly correlated to plasma aldosterone ( P = 0.026; R = 0.30), KCNJ5 mutations ( P = 0.0061; mutated 34:19 wild type), CYP11B2 ( P < 0.0001; R = 0.65), Purkinje cell protein 4 (PCP4; P < 0.0001; R = 0.53), and voltage-dependent calcium channels CaV1.3 ( P = 0.023; R = 0.31) and CaV3.2 ( P = 0.0019; R = 0.42). Based on our data, we hypothesize a possible role for VPREB3 in aldosterone biosynthesis, and present ideas for future functional studies. [ABSTRACT FROM AUTHOR]

Usually, benign tumors are not associated with an increased F-18 fluorodeoxyglucose (F-18 FDG) uptake on positron emission tomography (PET), although some exceptions have been reported in adrenal neoplasms. We present a rare case of adrenocortical oncocytoma associated with markedly increased FDG uptake, demonstrating a maximum standardized uptake value of 46.8. Histological examination demonstrated diffuse proliferation of tumor cells with eosinophilic and granular cytoplasm that were diffusely immunopositive for mitochondria and glucose transport protein 1, with focal and weak immunopositivity for 3β-hydroxysteroid dehydrogenase. Ultrastructural examination also revealed abundant mitochondria in the tumor cells. The tumor was diagnosed as adrenocortical oncocytoma and was considered benign according to Lin-Weiss-Bisceglia criteria. Diagnosis of adrenocortical oncocytoma can pose difficulties during both preoperative radiological and postoperative histopathological investigations. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinoma is a rare malignancy. Medical treatment including op'DDD or mitotane with or without platinum-based cytotoxic chemotherapy is frequently administered to the patients in an adjuvant setting following surgery or in advanced disease, because of aggressive clinical behavior in some cases. Potential roles of pathologists in determining the clinical algorithm of medical therapy are histopathological confirmation of adrenocortical carcinoma, both malignant features using the criteria of Weiss and adrenocortical origin applying immunohistochemistry of steroid factor-1 (SF-1); providing the relevant pathological information to determine the precise pathological stage in individual patients; and providing the accurate Ki67 labeling index of the patients. There are no established pathological surrogate markers for response to mitotane or op' DDD therapy available at this juncture but as in other malignancies, Ki67 LI could provide information as to the potential clinical response to platinum-based cytotoxic chemotherapy. Epidermal growth factor receptor (EGFR) is significantly overexpressed in adrenocortical carcinoma but the absence of gene mutations could limit the therapeutic application of anti-EGFR antibody and/or EGFR tyrosine kinase inhibitor in the patients. [ABSTRACT FROM AUTHOR]

Metallothionein-3 (MT-3) is an intracellular, low molecular weight protein mainly distributed in the central nervous system but also in various peripheral organs and several types of human neoplasms. However, details of MT-3 expression have not been examined in human adrenal cortex and its disorders. The mRNA levels of MT-3 were first evaluated by quantitative RT-PCR (qPCR) in adrenocortical aldosterone-producing adenoma (APA: 11) and cortisol-producing adenoma (CPA: 14). In addition, MT-3 immunohistochemistry was performed in non-pathological adrenal glands (NA: 19), idiopathic hyperaldosteronism (IHA: 10), APA (20), CPA (24), adjacent non-neoplastic adrenal glands of adenoma (AAG: 20), and adrenocortical carcinoma (ACC: 8). H295R cells were also treated with angiotensin-II or forskolin in a time-dependent manner, and the changes of MT-3 mRNA levels were evaluated by qPCR. Results of qPCR analysis demonstrated that MT-3 mRNA levels were significantly higher in APA than CPA ( P = 0.0004). MT-3 immunoreactivity was detected in the zona glomerulosa of NA, IHA, and AAG, as well as in APA, CPA, and ACC. When treated with angiotensin-II and forskolin, MT-3 mRNA levels reached a peak by 12 h in H295R cells, with significantly higher levels compared to control non-treated cells ( P < 0.01). The presence of MT-3 in the ZG of NA, IHA, and AAG, as well as APA may imply a role in the pathophysiology of aldosterone-producing tissues. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to evaluate the diagnostic ability of FDG PET/CT to predict the hormone-secretion status of lipid-rich adrenal tumors. Methods: This study included 29 lipid-rich (CT number <10 HU) adrenal tumors 2 cm or larger in diameter in 28 patients who underwent FDG PET/CT. The diagnoses were based on endocrine examinations, including adrenal venous sampling and subsequent surgical resection, or on the endocrinological and morphological imaging follow-up during a period of at least 6 months. The FDG uptake of the adrenal tumors was evaluated semi-quantitatively using maximum standardized uptake values (SUVmax) and a ratio of the adrenal SUVmax compared to the liver SUVmax (SUVratio) was used for comparison. The statistical significance of differences was assessed using the Mann-Whitney U test, and a p value <0.05 was considered to be statistically significant. Results: The lipid-rich adrenal tumors were proved to be 16 non-hormone-secreting tumors (15 adenomas and one myelolipoma) and 13 hormone-secreting tumors (five subclinical cortisol-producing adenomas, six aldosterone-producing adenomas and two adenomas that produced both cortisol and aldosterone). None of the patients had pheochromocytoma or a malignant adrenal tumor. The SUVmax (median, range) of the hormone-secreting tumors (3.2, 2.0-8.3) was higher than that of the non-hormone-secreting tumors (2.4, 1.8-3.3) ( p < 0.05). Similarly, the SUVratio of the hormone-secreting tumors (0.95, 0.70-3.10) was higher than that of the non-hormone-secreting tumors (0.72, 0.54-0.95) ( p < 0.01). There was no significant difference in the tumor diameter between the two groups ( p = 0.8). The sensitivity, specificity and accuracy of FDG PET/CT for differentiating hormone-secreting tumors from non-hormone-secreting tumors were 0.69, 0.81 and 0.76 for cutoff SUVratio of 0.8, and were 0.46, 1 and 0.76 for the cutoff SUVratio of 1.0, respectively. Conclusions: A lipid-rich adrenal tumor presenting increased FDG uptake compared with that of the liver is likely to be a hormone-secreting adenoma. Therefore, additional endocrinological investigations are strongly recommended when an FDG-avid lipid-rich incidentaloma is detected on FDG PET/CT. [ABSTRACT FROM AUTHOR]

Objective: We retrospectively examined the outcome of patients who underwent laparoscopic adrenalectomy for Cushing's/subclinical Cushing's syndrome in our single institute. Patients and methods: Between 1994 and 2008, a total of 114 patients (29 males and 85 females, median age 54 years) with adrenal Cushing's/subclinical Cushing's syndrome were studied. We compared the outcome of patients who underwent laparoscopic adrenalectomy between intraperitoneal and retroperitoneal approaches. Surgical complications were graded according to the Clavien grading system. We also examined the long-term results of subclinical Cushing's syndrome after laparoscopic adrenalectomy. Results: Laparoscopic surgical outcome did not differ significantly between patients with Cushing's syndrome and those with subclinical Cushing's syndrome. Patients who underwent laparoscopic intraperitoneal adrenalectomy had longer operative time than those who received retroperitoneal adrenalectomy (188.2 min vs. 160.9 min). However, operative blood loss and surgical complications were similar between both approaches. There were no complications of Clavien grade III or higher in either intraperitoneal or retroperitoneal approach. We confirmed the improvement of hypertension and glucose tolerance in patients with subclinical Cushing's syndrome after laparoscopic adrenalectomy. Conclusions: Laparoscopic adrenalectomy for adrenal Cushing's/subclinical Cushing's syndrome is safe and feasible in either intraperitoneal or retroperitoneal approach. The use of the Clavien grading system for reporting complications in the laparoscopic adrenalectomy is encouraged for a valuable quality assessment. [ABSTRACT FROM AUTHOR]

Primary aldosteronism (PA) is the most common cause of secondary hypertension, accounting for 10% of all hypertension. Far from being benign, hypertension due to PA is associated with high cardiovascular morbidity and mortality. However, PA is still underdiagnosed in general practice. Recent reports strongly recommend that identifying patients with PA is cost-beneficial based on improved cardiovascular outcomes afforded by specific surgical and medical treatment. This review provides an update of PA including controversial aspects of diagnosis and treatment. [ABSTRACT FROM AUTHOR]

drenomedullin 2/intermedin (AM2/IMD) is a new member of the calcitonin/calcitonin gene-related peptide (CGRP) family. CGRP, adrenomedullin (AM), and AM2/IMD share the receptor system consisting of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMP). The CRLR/RAMP2 or CRLR/RAMP3 complex forms the AM receptor, whereas the CRLR/RAMP1 forms the CGRP receptor. AM2/IMD binds non-selectively to all three CRLR/RAMP complexes. AM2/IMD has various actions, such as a potent vasodilator action and a protective action against oxidative stress, like AM and CGRP. When administered intracerebroventricularly, AM2/IMD stimulates the sympathetic nervous system and increases blood pressure. In human hypothalamus, AM2/IMD is expressed in the paraventricular and supraoptic nuclei and colocalized with arginine vasopressin. Anterior pituitary cells were diffusely immunostained for AM2/IMD. AM2/IMD stimulates the release of ACTH, prolactin, and oxytocin, but suppresses GH release. Some of these pituitary actions of AM2/IMD have been supposed to be mediated by an unidentified unique receptor for AM2/IMD. In the adrenal gland, immunoreactive (IR)-AM2/IMD and IR-AM were detected in the medulla, while the degree of IR-AM2/IMD and IR-AM in the cortex was relatively weak or undetectable. Furthermore, AM2/IMD and AM were expressed in adrenocortical tumors, such as aldosterone-secreting adenomas, and pheochromocytomas. CRLR and RAMPs are expressed in the hypothalamus, pituitaries, adrenal glands, and adrenal tumors. Thus, AM2/IMD is expressed in every endocrine organ of the hypothalamo-pituitary-adrenal axis together with its receptor. AM2/IMD may act as a neurotransmitter or modulator in the brain and as a paracrine/autocrine regulator in the hypothalamo-pituitary-adrenal axis. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinoma (ACC) is a rare neoplasm but some of the cases are highly malignant. Clinical outcome of the patients with advanced ACC still remained poor or dismal despite recent development of aggressive antitumor therapies. Target-specific therapies have been developed in a number of human malignancies and resulted in therapeutic benefits in some cancer patients. However, these therapies are only effective in the cases in which corresponding targets are expressed in tumor tissues. Therefore, we evaluated expression of potential surrogate markers using immunohistochemistry in archival materials of adrenocortical carcinoma in order to explore the potential application of target specific therapies in ACC in this study. We immunolocalized ten established or potential surrogate markers of target-specific therapies, located in the Ras/extracellular signal-regulated kinase and phosphatidylinositol-3 kinase/Akt pathways, in 41 ACC cases, 54 adrenocortical adenoma (ACA) cases, and five nonpathological adrenal glands and correlated the findings with clinicopathological factors of the patients. Among these markers examined, only epidermal growth factor receptor (EGFR) was significantly more abundant in ACC than in ACA ( P < 0.01). These findings suggest that the agents which specifically inhibit signal transductions through EGFR such as monoclonal antibodies against EGFR are considered to be worthwhile to be attempted in future clinical studies. [ABSTRACT FROM AUTHOR]

Primary aldosteronism is defined as secondary hypertension accompanied by aldosterone hypersecretion that leads to suppressed plasma renin, hypokaremia and hypertension. Primary aldosteronism occurs in 3-15% of hypertensive patients and is commonly caused by aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism (IHA). APA is usually treated by adrenalectomy, whereas IHA is best managed medically. Therefore, it is important to distinguish between unilateral and bilateral disease. Computed tomography (CT) is used to differentiate the subtypes. Even when multidetector CT is used, the detection rate of APAs of 1 cm or less is lower than 60% for the following reasons: (a) aldosterone secretion does not depend on tumor size, (b) a tumor may exist without lipid-rich cells, and (c) non-functioning unilateral adenomas are not uncommon, especially in older patients. Adrenal venous sampling is the gold standard for the differentiation of unilateral from bilateral disease in patients with primary aldosteronism. It is important to compare the laterality of aldosterone secretion by performing simultaneous bilateral blood collection 15 min following adrenocorticotropic hormone stimulation. The value of (aldosterone/cortisol)(side)/(aldosterone/cortisol)(contralateral side) provides the best discrimination between patients with and without APA. [ABSTRACT FROM AUTHOR]

We describe a case of mesangial proliferative glomerulonephritis (MesPGN), the clinical symptoms of which were exacerbated by aldosterone-producing adenoma (APA). A 45-year-old man, who had had a history of hypertension for several years, presented with renal derangement, with serum creatinine at its upper normal limit and with microhematuria and proteinuria. He also presented with hypokalemia, with a plasma aldosterone concentration at its upper normal limit and plasma renin activity at its lower normal limit. After the administration of spironolactone, we resected his left adrenal gland, which had a nodular lesion as well as aldosterone hypersecretion. The treatment normalized his arterial blood pressure and serum potassium concentration. Although his proteinuria disappeared with the reduction in arterial blood pressure, the microhematuria continued. The administration of losartan because of the histological finding of MesPGN reduced the amount of hematuria. A dissociated response of hematuria and proteinuria to antihypertensive treatment indicated that MesPGN was coincidental with APA. [ABSTRACT FROM AUTHOR]

Context: 18-Oxocortisol (18-oxoF) is a derivative of cortisol (F) that is produced by aldosterone synthase (CYP11B2). The potential for this steroid as a biomarker for differentiating patients with aldosterone-producing adenoma (APA) from those with idiopathic hyperaldosteronism (IHA) has not been examined.Objectives: We measured 18-oxoF, aldosterone, and F in plasma from adrenal vein sampling (AVS) of patients with primary aldosteronism. We compared 18-oxoF levels and 18-oxoF/F ratios for their potential to differentiate APA from IHA.Design, Setting, and Subjects: This study measured 18-oxoF, F, and aldosterone in AVS obtained from patients with unilateral APA (14 cases) or bilateral IHA (seven cases, 14 samples total) using liquid chromatography-tandem mass spectrometry and RIA analyses.Results: The levels of 18-oxoF and the ratios of 18-oxoF/F, before and after ACTH stimulation, were significantly higher in blood-draining APA than in those from the contralateral adrenal glands and from adrenal glands with IHA.Conclusions: The 18-oxoF levels and ratios of 18-oxoF/F in AVS samples can be a clinically useful biomarker for differentiating APA from IHA and for determining the localization or lateralization of APA in patients with primary aldosteronism. [ABSTRACT FROM AUTHOR]