Paraneoplastic Cushing Syndrome in Gastrointestinal Neuroendocrine Tumour

Ectopic production of adrenocorticotropic hormone (ACTH) by gastrointestinal neuroendocrine tumours (NETs) is relatively uncommon. We report a rare case of a liver metastatic G1 low-grade NET of the intestine that induced hypercortisolism after surgical resection. A 50-year-old man was admitted for an intestinal obstruction caused by a tumour of the intestine. Paraneoplastic Cushing syndrome was diagnosed more than a year later following the appearance of cushingoid symptoms, despite stable disease according to RECIST criteria but chromogranin A increase. Ketoconazole and sandostatin medical treatment and liver chemoembolization never managed to control the hypercortisolism unlike the bilateral adrenalectomy. The identification and effective management of this uncommon statement of ectopic ACTH secretion is important to improve the patient’s prognosis and quality of life.

Mixed corticomedullary tumor accompanied by unilateral aldosterone-producing adrenocortical micronodules: A case report

Mixed corticomedullary tumors (MCMTs) are rare and comprise of medullary and cortical cells in a single adrenal tumor. The mechanisms underlying its development have not been fully elucidated. Here, we report a case of MCMT in a 42-year-old woman. Based on the preoperative clinical findings, the patient was diagnosed as having a pheochromocytoma with subclinical Cushing's syndrome. Postoperative pathological diagnosis revealed that the tumor demonstrated morphologically distinct medullary and cortical components, which produced catecholamines and cortisol, respectively. Hybrid tumor cells producing both catecholamines and cortisol were not detected. Adrenocorticotropic hormone (ACTH)-positive tumor cells were identified to be present in the pheochromocytoma. This ectopic production of ACTH can contribute to an autonomous cortisol production in a paracrine manner. In addition, micronodules producing aldosterone were detected in the adrenal tissue adjacent to the tumor. The simultaneous development of these two lesions may not be correlated with each other; however, this case confirms the importance of a detailed histopathological examination of the adrenal lesions harboring complicated hormonal abnormalities by providing pivotal and indispensable information on their pathogenesis and the possible interaction of the hormones produced in the adrenal gland.

Acromegaly with empty sella syndrome

Summary Acromegaly is a rare, chronic progressive disorder with characteristic clinical features caused by persistent hypersecretion of growth hormone (GH), mostly from a pituitary adenoma (95%). Occasionally, ectopic production of GH or growth hormone-releasing hormone (GHRH) with resultant GH hypersecretion may lead to acromegaly. Sometimes localizing the source of GH hypersecretion may prove difficult. Rarely, acromegaly has been found in patients with an empty sella (ES) secondary to prior pituitary radiation and/or surgery. However, acromegaly in patients with primary empty sella (PES) is exceeding rarely and has only been described in a few cases. We describe a 47-year-old male who presented with overt features of acromegaly (macroglossia, prognathism, increased hand and feet size). Biochemically, both the serum GH (21.6 μg/L) and insulin-like growth factor 1 (635 μg/L) were elevated. In addition, there was a paradoxical elevation of GH following a 75 g oral glucose load. Pituitary MRI demonstrated an ES. In order to exclude an ectopic source of GH hypersecretion, further biochemical tests and imaging were done, which were unremarkable. Notably, increased uptake in the sella turcica on the 68Gallium DOTATATE PET/CT confirmed the ES as the likely source of GH secretion. As no overt lesion was noted, medical treatment (octreotide acetate) was initiated with a good clinical and biochemical response. At his 3 month follow-up, he reported an improvement in symptoms (fatigue and headache), however he still complained of low libido. Due to a persistently low testosterone level at follow-up, a long-acting testosterone was initiated. His GH level normalised, and IGF-1 has significantly reduced. Learning points The commonest cause of acromegaly is due to GH hypersecretion from pituitary adenomas (95%). Acromegaly has rarely been found in patients with ES. It is important to exclude a past history suggestive of pituitary apoplexy. Extra-pituitary source of GH such as ectopic production of GHRH with resultant GH hypersecretion needs to be excluded. In such cases, since there is no resectable mass, medical therapy is the primary treatment option.

Syndrome of ectopic production of the adrenocorticotropic hormone with hypercorticism

The syndrome of the ectopic production of the adrenocorticotropic hormone (ACTH) presents a version of endogenous hypercorticism which is the most challenging one for diagnostics and treatment. The paper discusses a clinical case of the ACTH-ectopic syndrome diagnosed in an elderly female patient. Advanced age and ongoing long-term treatment may obscure the typical manifestations of a disease. At the same time, it is common for doctors to be less focused on identifying rare diseases when working with elderly patients. A combination of clinical signs (resistance to the antihypertensive therapy; poorly controlled glycemia; increasing weakness; hypokalemia and severe skin pigmentation) allowed for suspecting symptomatic hypertension. Doctors need to be alert and to identify rare diseases among patients of any age group. This case also demonstrates the productivity of a multidisciplinary approach (a team including cardiologists, endocrinologists, radiology specialists and surgeons).

Diverse Manifestation of Acromegaly With Suspicion of Ectopic GHRH Secretion. Report of Two Cases

Introduction: Acromegaly can rarely be caused by an ectopic production of GH or GHRH by various neoplasms, most commonly neuroendocrine tumors of pancreatic or pulmonary origin. Squamous cell carcinoma of the lung has not been associated with ectopic GHRH secretion yet. The authors present two cases of acromegaly with suspicion of GHRH ectopy. Presentation of the Cases: Case 1. A male born in 1945 presenting with typical morphologic features of acromegaly. Pituitary MRI revealed a cuneatic-shaped, hypointense focal lesion (8x7x6 mm) in the right posterior part of the anterior pituitary lobe, radiologically interpreted as either hyperplasia of the intermediate lobe or atypical adenoma in a normal-sized pituitary. IGF-1 and no suppression of GH secretion after oral glucose load were observed. Furthermore, a polycyclic tumor in the 2nd segment of the right lung with pathological metabolic activity in 18FDG- PET/CT was discovered. Ga68- DOTA TATE PET/CT revealed no pathological accumulation of the tracer. After upper right lobectomy, squamous cell carcinoma, non-keratinizing, G3, with a negative immunohistochemical reaction for GH was confirmed. IHC for GHRH and serum GHRH have been scheduled. After surgery and chemotherapy, no biochemical remission of acromegaly was observed and the pituitary MRI showed stable radiological image of the pituitary tumor, suggesting rather a possible metastasis to the pituitary. Due to unfavorable prognosis, the patient was disqualified from neurosurgical resection of the pituitary tumor. Case 2. a male born in 1948 with typical symptoms of acromegaly, elevation of IGF-1 and no suppression of GH in OGTT. Due to MRI contraindications, only CT of the head was performed- it revealed partially empty sella, compressed pituitary with maximal diameter 3 mm and no focal lesions. Treatment with somatostatin analogue was introduced, however, only partial biochemical control was achieved. Ga68- DOTA TATE PET/CT performed after 8 years showed pathological expression of somatostatin receptors in the pancreatic tail. Abdominal CT confirmed a focal lesion in this location, 14x9 mm, with a strong enhancement after contrast administration, suggesting a neuroendocrine tumor. The patient refused to undergo any invasive procedures and remains treated with SRL. Serum GHRH has been scheduled. Conclusion: The authors report two cases of ectopic acromegaly suspicion, with an ambiguous clinical and radiological presentation. In unclear cases of acromegaly, ectopic production of GHRH should be taken into consideration.

Spatial control of potato tuberisation by the TCP transcription factor BRANCHED1b

The control of carbon allocation, storage and usage is critical for plant growth and development and is exploited for both crop food production and CO2 capture. Potato tubers are natural carbon reserves in the form of starch that have evolved to allow propagation and survival over winter. They form from stolons, below ground, where they are protected from cold temperatures and animal foraging. We show that BRANCHED1b (BRC1b) acts as a tuberisation repressor in aerial axillary buds, which prevents buds from competing in sink strength with stolons. BRC1b loss of function leads to ectopic production of aerial tubers and reduced underground tuberisation. In buds, BRC1b promotes dormancy, ABA signalling and downregulation of plasmodesmata gene expression. This limits sucrose unloading and access of the tuberigen factor SP6A to axillary buds. Moreover, BRC1b directly interacts with SP6A and blocks its tuber-forming activity in aerial nodes. Altogether these actions help promote tuberisation underground.

Hypercalcaemia in a dog with lymphoma without increases in parathyroid hormone, parathyroid hormone-related protein and vitamin D metabolites concentrations

Lymphoma is one of the most common causes of hypercalcaemia in dogs. Typically, the hypercalcaemic state is driven by ectopic production of parathyroid hormone-related protein by the malignant lymphoma cells. In this case report, the authors describe the diagnosis of lymphoma in a dog with hypercalcaemia which had a plasma parathyroid hormone-related protein concentration within the reference range. Furthermore, circulating concentrations of the two other main hormones which are known to increase serum calcium concentrations, namely parathyroid hormone and 1,25 dihydroxyvitamin D, were also below the upper limits of their respective reference ranges. This case report highlights that hypercalcaemia is not invariably mediated by increases in circulating concentrations of parathyroid hormone-related protein. In addition, it emphasises the need to further investigate the pathophysiology of malignancy-related hypercalcaemia in dogs.

Disseminated Strongyloides stercoralis Infection Associated with Endogenous Hypercortisolism – A Case Report

Patients with Strongyloides stercoralis infections are usually asymptomatic but massive hyperinfection may occur in patients with diseases associated with abnormal cell-mediated immunity or receiving immunosuppressive therapy. The authors present the clinical case of a 49-year-old man with a history of diarrhoea and cramping abdominal pain, generalized oedema, petechial rash, melanoderma, cough and dyspnoea. He presented hypokalaemia and arterial hypertension and was admitted with the diagnostic hypothesis of Cushing’s syndrome or adrenocorticotropic hormone ectopic production. The patient developed respiratory failure associated with bilateral lung opacities and was admitted to the Intensive Care Unit. The abdominal computed tomography scan revealed liver and duodenal masses. The duodenal biopsy showed the presence of Strongyloides stercoralis and the liver biopsy showed the presence of small cell neuroendocrine carcinoma. The patient died 50 days after hospital admission. The high level of endogenous cortisol observed in this patient may have facilitated the progression to severe fatal infection.

Ectopic Prolactin Secretion From a Uterine Leiomyoma

Ectopic hormone production is well recognized, but ectopic production of prolactin has been reported infrequently. We report here the case of a 47-year-old woman who had hyperprolactinemia (213-224 ng/mL) causing galactorrhea and hypogonadism. Cabergoline treatment, 1.0 mg twice a week, did not lower the prolactin level at all, but excision of a large uterine leiomyoma corrected the hyperprolactinemia and the hypogonadism. The excised leiomyoma tissue exhibited immunostaining for prolactin, confirming by this method for the first time that a uterine leiomyoma was the cause of hyperprolactinemia. This case illustrates the need to consider an ectopic source of prolactin in a patient who has hyperprolactinemia that is not associated with a large sellar mass and is completely resistant to cabergoline.

HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair

The tumor suppressor BRCA2 is essential for homologous recombination (HR), replication fork stability and DNA interstrand crosslink (ICL) repair in vertebrates. We show that ectopic production of HSF2BP, a BRCA2-interacting protein required for meiotic HR during mouse spermatogenesis, in non-germline human cells acutely sensitize them to ICL-inducing agents (mitomycin C and cisplatin) and PARP inhibitors, resulting in a phenotype characteristic of cells from Fanconi anemia (FA) patients. We biochemically recapitulate the suppression of ICL repair and establish that excess HSF2BP compromises HR by triggering the removal of BRCA2 from the ICL site and thereby preventing the loading of RAD51. This establishes ectopic expression of a wild-type meiotic protein in the absence of any other protein-coding mutations as a new mechanism that can lead to an FA-like cellular phenotype. Naturally occurring elevated production of HSF2BP in tumors may be a source of cancer-promoting genomic instability and also a targetable vulnerability.