Adrenocortical tumor (ACT) is a rare malignant tumor which usually present with Cushing syndrome and virilization. Paraneoplastic syndromes (PNS) due to neoplasms can occur with peptides or cytokines secreted by the tumor. Here, we report a 13-month-old-male presented with severe masculinization. He had signs of precocious puberty with enlarged testicles, very high testosterone levels but low levels of gonadotrophins, and elevated β-hCG. He underwent a left nephrectomy. The histopathological evaluation revealed a diagnosis of adrenocortical neoplasm. The levels of androgens and β-hCG normalized after the resection of tumor, and the clinical findings improved within few months. We report the first pediatric patient with peripheral precocious puberty due to an ACT that secretes β-hCG as PNS. A β-hCG secreting ACT can cause severe virilization due to increased gonadal androgens stimulated by β-hCG as well as due to increased adrenal androgens from the tumor.

Ectopic Cushing's syndrome due to ectopic ACTH&CRH-secreting by pheochromocytoma is extremely rare and can be fatal if not properly diagnosed. It remains unclear whether a unique cell type is responsible for multiple hormones secreting. In this work, we performed single-cell RNA sequencing to three different anatomic tumor tissues and one peritumoral tissue based on a rare case with ectopic ACTH&CRH-secreting pheochromocytoma. And in addition to that, three adrenal tumor specimens from common pheochromocytoma and adrenocortical adenomas were also involved in the comparison of tumor cellular heterogeneity. A total of 16 cell types in the tumor microenvironment were identified by unbiased cell clustering of single-cell transcriptomic profiles from all specimens. Notably, we identified a novel multi-functionally chromaffin-like cell type with high expression of both POMC (the precursor of ACTH) and CRH, called ACTH+&CRH + pheochromocyte. We hypothesized that the molecular mechanism of the rare case harbor Cushing's syndrome is due to the identified novel tumor cell type, that is, the secretion of ACTH had a direct effect on the adrenal gland to produce cortisol, while the secretion of CRH can indirectly stimulate the secretion of ACTH from the anterior pituitary. Besides, a new potential marker (GAL) co-expressed with ACTH and CRH might be involved in the regulation of ACTH secretion. The immunohistochemistry results confirmed its multi-functionally chromaffin-like properties with positive staining for CRH, POMC, ACTH, GAL, TH, and CgA. Our findings also proved to some extent the heterogeneity of endothelial and immune microenvironment in different adrenal tumor subtypes.

Cushing's syndrome (CS) is a set of clinical symptoms which occur as a result of hypercortisolemia. Endogenous ACTH-dependent CS related to an ectopic ACTH-secreting tumour constitutes 12%-17% of CS cases and is one of the most common causes of paraneoplastic syndromes. This study presents a case of a 31 year-old man with diabetes, hypertension, rosacea, purple stretch marks and hypokalemia. Findings of diagnostic procedures include high concentrations of cortisol and ACTH, pituitary microadenoma and a tumour in the anterior mediastinum. Dynamic hormone tests determined the source of excess hormone secretion and ectopic ACTH-dependent CS was diagnosed. Due to increasing symptoms of superior vena cava syndrome, an emergency resection of almost the whole tumour was performed, with only a small part of the upper pole left because of the proximity of large vessels and a risk of damaging them. On the basis of histopathological tests, an atypical carcinoid tumour of the thymus was identified. Immediately after the surgical procedure, there was a significant reduction of clinical and laboratory traits of hypercortisolemia, yet, during the 46 weeks of postoperative observation, despite chemotherapy, the progression of residual masses of the tumour occurred with metastases and increased hormone indices. The presented case shows and discusses the differentiation of ACTH-dependent hypercortisolemia and its causes, difficulties in surgical therapy and chemotherapy, as well as prognosis for atypical carcinoid of the thymus, which is a rare disease.

ACTH-ectopic syndrome is a severe, multiple-symptom disease characterized by secretion of adrenocorticotropic hormone (ACTH) by ectopic tumor, increased release of adrenal cortical hormones and clinical picture of hypercorticism. Diagnosis and treatment of ACTH-ectopic syndrome is still difficult problem despite the achievements of modern medicine. There are several unresolved issues including optimal diagnostic algorithm, indications for various surgical procedures and their optimal dates. This review is devoted to these questions.

A 74-year old man presented to us with difficulty urinating. The laboratory examinations revealed an elevated prostate-specific antigen (PSA) level. A prostate biopsy revealed prostate adenocarcinoma. The computed tomography scan showed metastasis to lymph nodes in the pelvic cavity and both adrenal glands. Combined androgen blockade therapy was started, and PSA levels began to decrease gradually. However, 2 months later, he was hospitalized for treatment of cellulitis and was found to have hypertension, hyperglycemia, and hypokalemia. Endocrinological studies showed elevated serum adrenocorticotropic hormone (ACTH) and serum and urinary cortisol levels. The plasma cortisol level was not reduced by either the 1 mg or 8 mg dexamethasone suppression test, and the plasma cortisol and ACTHlevels did not respond to the corticotropin-releasing hormone test. Computed tomography indicated increased metastasis, and endocrinological studies and other examinations suggested a diagnosis of ectopic ACTHsyndrome. Combined androgen blockade therapy was continued, and inhibitors of adrenocortical synthesis were also administered. However, 16 weeks later, he died of prostate cancer. On autopsy, the histological examination revealed small cell carcinoma in the prostate and adrenal glands and other sites of metastasis, while immunohistochemistry findings revealed that the tumors in the prostate and adrenal glands were strongly positive for ACTH.

A 62-year-old woman was admitted for evaluation of an incidentally discovered adrenal mass and hypertension. CT scan revealed a 7 cm mass in the right adrenal gland. After careful examination, the patient was diagnosed with subclinical hypercortisolism (SH). Adrenalectomy was performed. Histopathological examination showed an adrenocortical adenoma. Symptoms and signs of myasthenia gravis appeared 5 months later. CT of the chest showed a solid tissue mass in the mediastinum. The patient underwent a sternotomy with excision of the tumor, which histologically proved to be a type 2B thymoma. We describe a rare case of SH due to an incidentally discovered adrenocortical adenoma in a patient who manifested myasthenia gravis after surgical remission of the cortisol excess.

Primary aldosteronism (PA) is the most common and curable form of secondary hypertension. It is caused in the majority of cases by either unilateral aldosterone overproduction due to an aldosterone-producing adenoma (APA) or by bilateral adrenal hyperplasia. Recent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA and familial hyperaldosteronism. Recurrent somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and ATPases (ATP1A1 and ATP2B3) regulating intracellular ionic homeostasis and cell membrane potential have been identified in APA. Similar germline mutations of KCNJ5 were identified in a severe familial form of PA, familial hyperaldosteronism type 3 (FH3), whereas de novo germline CACNA1D mutations were found in two cases of hyperaldosteronism associated with a complex neurological disorder. These results have allowed a pathophysiological model of APA development to be established. This model involves modifications in intracellular ionic homeostasis and membrane potential, accounting for ∼50% of all tumors, associated with specific gender differences and severity of PA. In this review, we describe the different genetic abnormalities associated with PA and discuss the mechanisms whereby they lead to increased aldosterone production and cell proliferation. We also address some of the foreseeable consequences that genetic knowledge may contribute to improve diagnosis and patient care.

Myasthenia gravis (MG) is an autoimmune disorder generally mediated by antibodies against the acetylcholine receptors of the skeletal muscles. Depending on the disease burden, MG patients may experience chronic dysregulation of both the hormonal stress axis and the immune system, consequently, aggravating the disease itself but also leading to secondary psychopathological abnormalities. A long-term clinical course requires long-term glucocorticoid (GC) therapy, which may change the psychological state by affecting the pituitary-adrenocortical system in MG patients. In this study, we investigated the function of the pituitary-adrenocortical system in MG patients who were treated with prednisolone (PSL) and evaluated their quality of life by using the Medical Outcomes Study 36-item Short-Form Health Survey and the 28-item general health questionnaire (GHQ-28). ACTH and cortisol levels in the plasma of patients who were treated with PSL (PSL[+] group, n = 18) were lower than those in the plasma of patients who were treated without PSL (PSL[-] group, n = 29; P < 0.05 and P < 0.01, respectively). In the PSL(+) group, we confirmed that cortisol levels negatively correlated with daily PSL dosages (P < 0.05). The anxiety and depression scores from the GHQ-28 in the PSL(+) group were lower than those in the PSL(-) group (P < 0.05, respectively). There was no significant correlation between cortisol levels and corticotropin levels in plasma of the PSL(-) group. However, we confirmed that corticotropin levels positively correlated with cortisol levels in plasma (P < 0.01) and negatively correlated with anxiety/insomnia scores from the GHQ-28 (P < 0.05) in the PSL(+) group. In conclusion, low-dose GC treatment complemented the pituitary-adrenocortical system and improved the psychological state in MG patients.

We report the case of a patient with life-threatening Aspergillosis during paraneoplastic Cushing's syndrome. Anticortisolic drug ketoconazole was unable to lower severe hypercortisolism and despite antifungal treatment available at this time (liposomal amphotericine B and terbinafine), Aspergillus fumigatus infection was uncontrolled and extensive. "Rescue" bilateral adrenalectomy was performed to control hypercortisolism, leading to rapid fungal infection cure. We emphasize surgical management of hypercortisolism to achieve rapid blunting of cortisol production in a such life-threatening situation.

The aim of the study was analysis of preoperative diagnostics of patients who underwent laparoscopic adrenalectomy. In the preoperative diagnostics in 10 patients (22.2%) pheochromocytoma was found, in 8 (17.8%) Conn's syndrome, in 4 (8.9%) Cushing's syndrome and in 1 (2.2%) adrenal virilization. Full accordance between histopathological findings and preoperative diagnosis was achieved in 91% of cases. Four cases of discrepancy were: 1 false positive preoperative diagnosis of aldosteronoma, 1 false positive and 2 false negative diagnosis of pheochromocytoma.

Surgically correctable forms of primary aldosteronism are generally held to be less common than forms requiring medical therapy. However, with the availability of improved diagnostic techniques and the adoption of a systematic and thorough diagnostic work-up they can be identified more commonly than expected. Adrenal vein sampling (AVS) for measurement of cortisol and aldosterone has emerged as the 'gold standard' diagnostic test for identifying unilateral causes of primary aldosteronism that are amenable to surgical cure. Adrenalectomy can provide long-term normalisation of blood pressure and correction of primary aldosteronism in about 55% of patients with an aldosterone-producing adenoma and can markedly ameliorate blood pressure control in the rest. This chapter summarises the diagnostic work-up suggested for identifying these forms and examines the other diseases mimicking mineralocorticoid excess that enter into the differential diagnosis of surgically curable primary aldosteronism.

Spontaneous hyperadrenocorticism in dogs is known to be the result of excessive secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland or excessive autonomous glucocorticoid secretion by an adrenocortical tumor. Here, we report on an 8-year-old German shepherd dog in which ACTH-dependent hyperadrenocorticism was a result of ectopic ACTH secretion and could be related to an abdominal neuroendocrine tumor. Hyperadrenocorticism was diagnosed on the basis of the history, clinical signs, and elevated urinary corticoid/creatinine ratios (UCCRs; 236 and 350 x 10(-6); reference range < 10 x 10(-6)). The UCCR remained elevated (226 x 10(-6)) after three oral doses of dexamethasone (0.1 mg/kg body weight) at 8-h intervals. Ultrasonography revealed two equivalently enlarged adrenal glands, consistent with adrenocortical hyperplasia. Plasma ACTH concentration was clearly elevated (159 and 188 ng/l; reference range 5-85 ng/l). Computed tomography (CT) revealed that the pituitary was not enlarged. These findings were interpreted as indicating dexamethasone-resistant pituitary-dependent hyperadrenocorticism. Transsphenoidal hypophysectomy was performed but within 2 weeks after surgery, there was exacerbation of the clinical signs of hyperadrenocorticism. Plasma ACTH concentration (281 ng/l) and UCCRs (1518 and 2176 x 10(-6)) were even higher than before surgery. Histological examination of the pituitary gland revealed no neoplasia. Stimulation of the pituitary with corticotropin-releasing hormone did not affect plasma ACTH and cortisol concentrations. Treatment with trilostane was started and restored normocorticism. CT of the pituitary fossa, 10 months after hypophysectomy, revealed an empty sella. Hence, it was presumed that there was ectopic secretion of ACTH. CT of the abdomen revealed a mass in the region of the pancreas and a few nodules in the liver. Partial pancreatectomy with adjacent lymph node extirpation was performed and the liver nodules were biopsied. Histological examination revealed a metastasized neuroendocrine tumor. Abdominal surgery was not curative and medical treatment with trilostane was continued. At 18 months after the abdominal surgery, the dog is still in good condition. In conclusion, the combination of (1) severe dexamethasone-resistant hyperadrenocorticism with elevated circulating ACTH levels, (2) definitive demonstration of the absence of pituitary neoplasia, and (3) an abdominal neuroendocrine tumor allowed the diagnosis of ectopic ACTH secretion.