Aldosterone-producing Adrenocortical Carcinoma Research Articles

Progress on Genetic Basis of Primary Aldosteronism.

Primary aldosteronism (PA) is a heterogeneous group of disorders caused by the autonomous overproduction of aldosterone with simultaneous suppression of plasma renin activity (PRA). It is considered to be the most common endocrine cause of secondary arterial hypertension (HT) and is associated with a high rate of cardiovascular complications. PA is most often caused by a bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA); rarer causes of PA include genetic disorders of steroidogenesis (familial hyperaldosteronism (FA) type I, II, III and IV), aldosterone-producing adrenocortical carcinoma, and ectopic aldosterone-producing tumors. Over the last few years, significant progress has been made towards understanding the genetic basis of PA, classifying it as a channelopathy. Recently, a growing body of clinical evidence suggests that mutations in ion channels appear to be the major cause of aldosterone-producing adenomas, and several mutations within the ion channel encoding genes have been identified. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D) have been identified in nearly 60% of the sporadic APAs, while germline mutations in KCNJ5 and CACNA1H have been reported in different subtypes of familial hyperaldosteronism. These new insights into the molecular mechanisms underlying PA may be associated with potential implications for diagnosis and therapy.

Aldosterone-producing adrenocortical carcinoma with unusual initial presentations: A rare disease and case report

Aldosterone-producing adrenocortical carcinoma with unusual initial presentations: A rare disease and case report

Approach to the patient with aldosterone-producing adrenocortical carcinoma

Aldosterone-producing adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Only a few cases are reported in China. This systematic review investigated the diagnosis and treatment strategy of aldosterone-producing ACC through a recent case of the disease. A case of a 49-year-old female who diagnosed with aldosterone-producing ACC by hormonal assays, medical imaging and pathology. Her condition has been alleviated after surgery. Aldosterone-producing ACC is a rare malignancy with limited treatment options and surgery is the primary treatment strategy. (Chin J Endocrinol Metab, 2018, 34: 795-799) Key words: Adrenocortical carcinoma; Primary aldosteronism; Endocrine tumors

Aldosterone‐producing adrenocortical carcinoma with myxoid differentiation in a cat

A 10-year-old male neutered Persian cat was presented with an abdominal mass and history of weakness. Blood smear examination found marked elliptocytosis, and serum biochemical analysis revealed hypokalemia, hypochloremia, increased creatine kinase activity, and a high aldosterone concentration. Cytologic examination of the mass revealed neoplastic endocrine cells with moderate criteria of malignancy, favoring adrenocortical neoplasia. The adrenal mass was surgically excised and histologically characterized by lobules of mildly pleomorphic, polygonal neoplastic cells with moderate to abundant, occasionally granular, eosinophilic cytoplasm. Lobules were separated by fine fibrovascular trabeculae, and numerous cystic cavities containing amorphous eosinophilic material that stained positive with Alcian blue and periodic acid-Schiff were seen. Neoplastic cells were multifocally positive for cytochrome P450 aldosterone synthase. Based on clinicopathologic and immunohistochemical findings the present case was diagnosed as an aldosterone-producing adrenocortical carcinoma with myxoid differentiation. While this entity has not been reported in cats, myxoid differentiation of adrenocortical carcinomas has been found in other species and can pose a major diagnostic challenge on microscopic examination.

Genetic aspects of primary hyperaldosteronism.

Primary hyperaldosteronism (PHA) is the most common form of secondary hypertension of hormonal origin. It affects about 10% of all hypertensive patients. It is connected with increased morbidity and mortality from cardiovascular diseases (CVD) compared to patients with essential hypertension of a similar age. Usually, it is an effect of bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA), more rare causes of PHA are: unilateral adrenal hyperplasia, aldosterone-producing adrenocortical carcinoma, ectopic aldosterone-producing tumors and familial hyperaldosteronism. Recent genetic studies have thrown a new light on the pathogenesis of PHA, classifying it as a channelopathy. Several mutations within the ion channels encoding genes have been identified. A possible link between primary hyperaldosteronism and polymorphism of aldosterone synthase gene and ion channel genes is still being investigated. In this manuscript, we focus on genetic aspects of primary hyperaldosteronism, and present an up-to-date compilation of available data with the widened pathogenetic approach.

Aldosterone-producing adrenocortical carcinoma and alteration of secretion pattern on recurrence: a case report

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Predictors of malignancy in primary aldosteronism

Primary aldosteronism (PA, also Conn syndrome) is a benign disease in majority of cases. However, malignant transformation has been described. Present study reports on three cases of aldosterone producing adrenocortical carcinoma (APAC) in comparison to patients with benign PA. Data of patients undergoing adrenalectomy for benign PA were compared to patients with APAC. Retrospective chart analysis was performed. All patients received spironolactone for 6-8weeks preoperatively. Seventy-four patients underwent adrenalectomy for PA between 1994 and 2011. Three of them revealed an APAC. Patients with APAC presented with a significantly lower serum potassium level (1.7mmol/l vs. 3.4mmol/l, p = 0.001) and significant larger tumors (5.2 vs. 1.8cm, p = 0.002). In addition, aldosterone/renin (A/R) ratio 675 in patients with APAC as compared to 74 in patients with benign PA (p = 0.0001). Sixty-eight of 71 patients with benign PA underwent minimal invasive surgery, whereas all three patients with APAC were operated conventionally. All patients with APAC developed disease recurrence 6-18months postoperatively. Tumor size >4cm and a very high A/R ratio seems to predictors of malignancy in patients with PA. If these criteria are present, open adrenalectomy should be performed instead of endoscopic procedure.

A Case of Adrenocortical Oncocytoma Occurring with Aldosteronoma

A 48-yr-old woman was referred to our hospital for evaluation of a left adrenal mass. An abdominal computed tomography scan demonstrated a 5.4 3.7-cm tumor in the left adrenal gland (Fig. 1, A and B). She had untreated hypertension on admission and no Cushingoid features. When in a seated position, the patient’s urinary aldosterone excretion rate was 19.4 g/d, plasma aldosterone concentration (PAC) was 20.8 ng/dl, and plasma renin activity (PRA) was 0.8 ng/ml h mid morning. Her plasma aldosterone to renin ratio was 26.0. She was diagnosed with normokalemic (serum potassium, 3.8 mmol/ liter) primary aldosteronism after captopril challenge (PAC, 15.2 ng/dl; PRA, 0.4 ng/ml h at 2 h) and furosemide-plus-upright tests (PAC, 65.4 ng/dl; PRA, 0.3 ng/ ml h at 2 h) (1). 18F-Fluorodeoxyglucose (FDG) positron emission tomography demonstrated a marked uptake of FDG in the left adrenal mass (Fig. 1, C and D). The mass was therefore clinically diagnosed as an aldosterone-producing adrenocortical carcinoma (2). After left adrenalectomy, the patient’s hypertension improved with normalizationofaldosterone to renin ratio.Lightmicroscopic examination revealed the cells within the main tumor body to have abundant eosinophilic cytoplasm and three positive scores in Weiss criteria, namely, nuclear atypia, architecture, and an eosinophilic cytoplasm (Fig. 2A). The eosinophilic tumor cells were positive for steroidogenic factor-1, but negative for steroidogenic enzymes [3 -hydroxysteroid dehydrogenase (3BHSD), P450c21, P450c17, and dehydroepiandrosterone sulfotransferase]. This main tumor body was therefore diagnosed as a true nonfunctioning adrenocortical tumor, an “oncocytoma” (3). A wellcircumscribed localized mass of clear cortical cells demonstrating marked P450 side-chain cleavage enzyme, 3BHSD and P450c21, and weak P450c17 immunoreactivity was detected around one margin of the oncocytoma (Fig. 2, B–E).Theattachedzonaglomerulosawashyperplasticbut negative for 3BHSD, evidence pointing toward a nonfunctioning albeit hyperplastic response in the neighboring normal glomerulosa. This part was therefore histopathologically diagnosed as an aldosteronoma. Although it could be one tumor with heterogeneity, this is the first

Aldosterone-producing adenoma and other surgically correctable forms of primary aldosteronism

Surgically correctable forms of primary aldosteronism are characterized by unilateral aldosterone hypersecretion and renin suppression, associated with varying degrees of hypertension and hypokalemia. Unilateral aldosterone hypersecretion is caused by an aldosterone-producing adenoma (also known as Conn's adenoma and aldosteronoma), primary unilateral adrenal hyperplasia and rare cases of aldosterone-producing adrenocortical carcinoma. In these forms, unilateral adrenalectomy can cure aldosterone excess and hypokalemia, but not necessarily hypertension. The prevalence of primary aldosteronism in the general population is not known. Its prevalence in referred hypertensive populations is estimated to be between 6 and 13%, of which 1.5 to 5% have an aldosterone-producing adenoma or primary unilateral adrenal hyperplasia. Taking into account referral biases, the prevalence of surgically correctable primary aldosteronism is probably less than 1.5% in the hypertensive population and less than 0.3% in the general adult population. Surgically correctable primary aldosteronism is sought in patients with hypokalemic, severe or resistant forms of hypertension. Recent recommendations suggest screening for primary aldosteronism using the aldosterone to renin ratio. Patients with a raised ratio then undergo confirmatory suppression tests. The differential diagnosis of hypokalemic hypertension with low renin includes mineralocorticoid excess, with the mineralocorticoid being cortisol or 11-deoxycorticosterone, apparent mineralocorticoid excess, pseudo-hypermineralocorticoidism in Liddle syndrome or exposure to glycyrrhizic acid. Once the diagnosis is confirmed, adrenal computed tomography is performed for all patients. If surgery is considered, taking into consideration the clinical context and the desire of the patient, adrenal vein sampling is performed to detect whether or not aldosterone hypersecretion is unilateral. Laparoscopic surgery for unilateral aldosterone hypersecretion is associated with a morbidity of about 8%, with most complications being minor. It generally results in the normalization of aldosterone secretion and kalemia, and in a large decrease in blood pressure, but normotension without treatment is only achieved in half of all cases. Normotension following adrenalectomy is more frequent in young patients with recent hypertension than in patients with long-standing hypertension or a family history of hypertension.

A rare cause of secondary hypertension.

A 20-year-old obese man was referred to our hospital with 1-year hypertension and mild hypokalaemia (potassium, 3.3 mmol/l). The ratio of postcaptopril plasma aldosterone concentration (PAC) to plasma renin activity (PRA) was high [25.8 (ng/dl)/0.33 (ng/ml/h) = 77.4]. The PAC postsaline loading test remained high (28.1 ng/dl). The 24-h urinary catecholamines and VMA (vanillyl mandelic acid) were within normal limits. Primary aldosteronism was diagnosed, and a computed tomography disclosed an isodense mass with a maximal diameter of 4 cm over the right adrenal gland (Figure ​(Figure1).1). The patient then underwent right laparoscopic adrenalectomy. Grossly, a well-encapsulated 4.5 × 4.0 × 3.5 cm yellowish tumour with central necrosis was noted. Histologically, the tumour was composed of pleomorphic cells with high-grade nuclei, prominent nucleoli, and >1/3 of the tumour presenting patternless sheets of cells. Furthermore, the mitotic count was >5 in 50 high power fields with atypical mitotic figures (Figure ​(Figure2a2a and b). Adrenocortical carcinoma (ACC) was diagnosed according to the modified Weiss classification system [1]. Subsequent immunohistochemical studies confirmed that the tumour was aldosterone producing (Figure ​(Figure2c2c and d). Two months after the operation, PAC and PRA were 32.7 ng/dl and 25.45 ng/ml/h, respectively, and the patient became normotensive. Fig. 1 Adrenal tumour. Non-contrast CT scan shows an oval tumour, 4 cm in diameter, in the right adrenal region. Fig. 2 Histopathology of adrenocortical carcinoma. (a) Pleomorphic tumour cells form patternless sheets of cells. (b) Tumour cells with eosinophilic cytoplasm, high nuclear grade and atypical mitotic figures (arrows) (haematoxylin and eosin stain, 100×; ... ACCs are rare and account for an estimated 0.05–0.2% of all malignancies [2]. Hormonally functioning tumours occur in ∼50% of ACC patients. Nevertheless, the aldosterone-producing ACC are even rarer. There is a bimodal occurrence by age, with a peak incidence at 4 cm should raise clinical suspicion of adrenocortical malignancy, even at a young age.

Urinary Aldosterone to Creatinine Ratio in Cats before and after Suppression with Salt or Fludrocortisone Acetate

The endocrine diagnosis of primary hyperaldosteronism in cats currently is based on an increased plasma aldosterone to renin ratio, which has several disadvantages for use in veterinary practice. To establish a reference range for the urinary aldosterone to creatinine ratio (UACR) and to determine whether oral administration of either sodium chloride or fludrocortisone acetate is effective for use in a suppression test. Forty-two healthy cats from an animal shelter and 1 cat with primary hyperaldosteronism from a veterinary teaching hospital. Morning urine samples for determination of the basal UACR were collected from 42 healthy cats. For the suppression tests, urine samples for the UACR were collected after twice daily oral administration for 4 consecutive days of either sodium chloride, 0.25 g/kg body weight (n = 22) or fludrocortisone acetate, 0.05 mg/kg body weight (n = 15). The median basal UACR was 7.2 x 10(-9) (range, 1.8-52.3 x 10(-9)), with a calculated reference range of < 46.5 x 10(-9). Administration of sodium chloride resulted in adequate salt loading in 10 of 22 cats, but without significant reduction in the UACR. Administration of fludrocortisone resulted in a significant decrease in the UACR (median, 78%; range, 44-97%; P < .001) in healthy cats. In the cat with an aldosterone-producing adrenocortical carcinoma, the basal UACR and the UACR after fludrocortisone administration were 32 x 10(-9) and 36 x 10(-9), respectively. Using the UACR for an oral fludrocortisone suppression test may be useful for the diagnosis of primary hyperaldosteronism in cats.

A Case Report of an Aldosterone-producing Adrenocortical Carcinoma

Primary aldosteronism is a syndrome characterized by hypokalemic alkalosis and hypertension. Aldosteroneproducing adenomas and bilateral adrenal hyperplasia are common causes of this syndrome. An aldosteroneproducing adrenocortical carcinoma is a very rare cause of primary aldosteronism. Recently we experienced a case of an aldosterone-producing adrenocortical carcinoma. A 41-year-old female was admitted for evaluation of a retroperitoneal mass. Because of hypokalemia and a history of hypertension, we evaluated the patient for primary aldosteronism. The high ratio of plasma aldosterone to renin activity suggested the possibility of the presence of primary aldosteronism. We performed adrenal vein sampling for differential diagnosis of an aldosterone-producing tumor from a retroperitoneal mass. The adrenal vein sampling showed that the primary aldosteronism was due to an aldosterone-producing tumor from the left adrenal gland. Surgical findings indicated that the retroperitoneal mass originated from the left adrenal gland and the pathologic al diagnosis for the mass was an adrenocortical carcinoma. In conclusion, the results from the adrenal vein sampling, as well as the surgical and pathological findings demonstrate that this case was an aldosterone-producing adrenocortical carcinoma. (J Kor Endocr Soc 23:56~61, 2008)

Aldosterone-producing adrenocortical carcinoma: an unusual cause of Conn’s syndrome with an ominous clinical course

Aldosterone-producing adrenocortical carcinoma (APAC) is a rare cause of hypertension often diagnosed late because of paucity of information. Thus, we delineated its clinical course and survival rates based on two cases referred to us that featured diverging clinical courses, and on a scrutiny of the literature since 1955 when the first case of APAC was identified. Data on demography, imaging results, hormonal assessment, histology, and clinical course were extracted independently by the investigators. We included in our database 58 cases, most presenting with Conn's syndrome. Plasma aldosterone levels were on average increased 14-fold; plasma renin activity was suppressed in 55% of cases. The tumor showed extremely variable size and weight, and no gender or side preference. Metastases were present in 10% of all cases at initial diagnosis and in an additional 48% of cases at follow-up. Median survival was 546 days (95% confidence interval (CI): 240-851); median time to either recurrence or death was 212 days (95% CI: 29-395). No clinical or histological signs predicted survival with Cox regression analysis. We concluded that, although an ominous course with a poor survival rate is common, no sign accurately predicts the course of APAC. Thus, molecular studies to identify diagnostic markers of survival are mandatory.

Conn’s syndrome caused by aldosterone-producing adrenocortical carcinoma: report of two divergent cases and a meta-analysis of all reported cases since 1955

Aldosterone-producing adrenocortical carcinoma (APAC) is a rare disorder: hence, as a result of the paucity of information on its biological behaviour, the diagnosis is often delayed. To date, no data on survival rates and diagnostic markers signs of malignancy is available. To report on two cases that featured an unusual course and to delineate the clinical characteristics and natural history of APAC based on a meta-analysis of all reported cases from the literature since 1955. A database was created with all available information on demography, imaging results, hormonal data, gross features, histology, and clinical course. We used Kaplan Meier and Cox regression analysis to calculate survival curves and recurrence-free survival, and to identify the impact of several covariates on survival. We identified in the literature 62 cases of APAC, including the present two, all presenting the classical signs of Conn's syndrome. Plasma aldosterone levels exhibited on average a 14-fold increase; plasma renin activity was suppressed in 55% of cases. The tumour showed no gender or side preference and extremely variable size and weight. At the time of initial diagnosis metastases were present in 10% of all cases; they were detected at follow-up in 48% additional cases. Median survival was 546 days (95% c.i.: 240–851); median time to either recurrence or death was 212 days (95% c.i.: 29–395). Neither clinical signs nor histological features of malignancy did predict survival. The clinical features of APAC are variable, but an ominous clinical course with a very poor survival rate is common. No clinical signs were found to accurately predict malignant clinical course. Hence, molecular studies to identify diagnostic markers and predictors of survival are mandatory.

Cytochrome P450-catalyzed binding of 3-methylsulfonyl-DDE and o,p'-DDD in human adrenal zona fasciculata/reticularis.

3-Methylsulfonyl-2,2'-bis(4-chlorophenyl)-1,1'-dichloroethene (MeSO(2)-DDE) is a potent, tissue-specific toxicant that induces necrosis of the adrenal zona fasciculata following a local CYP11B1-catalyzed activation to a reactive intermediate in mice. Autoradiography was used to examine CYP11B1-catalyzed binding of MeSO(2)-[(14)C]DDE and the adrenocorticolytic drug 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichlorethane; (o,p'-[(14)C]DDD, Mitotane, Lysodren) in human adrenal tissue slice culture. Both compounds gave rise to a selective binding in the one sample of normal adrenal zona fasciculata/reticularis, leaving zona glomerulosa and the adrenal medulla devoid of binding. Addition of the CYP11B1 selective inhibitor metyrapone (50 microM) reduced MeSO(2)-[(14)C]DDE binding below the detection limit, whereas o,p'-[(14)C]DDD binding was reduced only by 42%. Selective binding of MeSO(2)-[(14)C]DDE and o,p'-[(14)C]DDD was also observed in an aldosterone-producing adrenocortical carcinoma and in a nonfunctional adrenocortical hyperplasia. Exposure of slices from the normal adrenal cortex to MeSO(2)-DDE (25 microM) resulted in an increased accumulation of 11-deoxycorticosterone, 11-deoxycortisol and androstenedione in the medium, and exposure to o,p'-DDD (25 microM) did not alter the steroid secretion pattern. No histological changes were found in either MeSO(2)-DDE- or o,p'-DDD-exposed slices, compared with nonexposed slices. We suggest that MeSO(2)-DDE might act as a potent adrenocorticolytic agent in humans. Further studies are needed to establish the usefulness of MeSO(2)-DDE as a possible alternative for the treatment of adrenocortical hypersecretion and tumor growth.

Plasma Immunoreactive Proopiolipomelanocortin-Derived Peptides in Patients with Primary Hyperaldosteronism, Idiopathic Hyperaldosteronism with Bilateral Adrenal Hyperplasia, and Dexamethasone-Suppressible Hyperaldosteronism*

Immunoreactive plasma levels of the proopiolipomelanocortin-derived peptides, ACTH, beta-endorphin-lipotropin, and gamma 3MSH, were measured in patients with primary hyperaldosteronism, idiopathic hyperaldosteronism with bilateral adrenal hyperplasia, and dexamethasone-suppressible hyperaldosteronism. Plasma peptide concentrations in patient groups were not different from those in normal controls. Removal of aldosterone-producing adenomas in three patients and of an aldosterone-producing adrenocortical carcinoma in one patient did not affect plasma peptide concentrations. Furthermore, infusion of the opiate antagonist naloxone (0.2 mg/min) in one patient with bilateral adrenal hyperplasia had no effect on either plasma aldosterone or cortisol. These results suggest that the proopiolipomelanocortin-derived peptides are not overproduced in states of hyperaldosteronism.

The mineralocorticoid hormone pathways in hypertension with hyperaldosteronism.

Simultaneous measurement of the 0800-hr plasma concentrations of deoxycorticosterone (DOC), corticosterone (B), 18-hydroxycorticosterone (18-OHB), aldosterone, 18-hydroxydeoxycorticosterone (18-OHDOC) and cortisol (F) in four types of primary aldosteronism provides evidence for primary adrenal disease. Elevated DOC with normal F concentrations in the presence of elevated 18-OHB and aldosterone, and suppressed renin concentration suggests a primary adrenal abnormality of the zona glomerulosa (ZG). Steroid production by the zona fasciculata (ZF), F, 18-OHDOC, and most often B, is normal. These patterns exist only for primary adrenal hyperplasia, aldosterone-producing adenoma (APA), and aldosterone-producing adrenocortical carcinoma (AP-Ca). Elevated DOC levels are rarely found in patients with idiopathic hyperaldosteronism (IHA or adrenal hyperplasia) and suggest that IHA is not a primary adrenal disorder and should be excluded from the syndrome of primary aldosteronism as they have been heretofore.