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      pNET co-secreting GHRH and calcitonin: ex vivo hormonal studies in human pituitary cells


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          Acromegaly due to ectopic GHRH secretion from a neuroendocrine tumor (NET) is rare and comprises <1% of all acromegaly cases. Herein we present a 57-year-old woman with clinical and biochemical features of acromegaly and a 6 cm pancreatic NET (pNET), secreting GHRH and calcitonin. Following surgical resection of the pancreatic tumor, IGF1, GH and calcitonin normalized, and the clinical features of acromegaly improved. In vitro studies confirmed that the tumor secreted large amounts of both GHRH and calcitonin, and incubation of pNET culture-derived conditioned media stimulated GH release from a cultured human pituitary adenoma. This is a unique case of pNET secreting both GHRH and calcitonin. The ability of the pNET-derived medium to stimulate in vitro GH release from a human pituitary-cell culture, combined with the clinical and hormonal remission following tumor resection, confirmed the ectopic source of acromegaly in this patient.

          Learning points

          • Signs, symptoms and initial work-up of acromegaly due to ectopic GHRH secretion are similar to pituitary-dependent acromegaly. However, if no identifiable pituitary lesion is found, somatostatin receptor scan and further imaging (CT, MRI) should be performed.

          • Detection of GHRH in the blood and in the tumor-derived medium supports the diagnosis of ectopic GHRH secretion.

          • Functional bioactivity of pNET-secreted GHRH can be proved in vitro by releasing GH from human pituitary cells.

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          Most cited references10

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          Ectopic acromegaly due to growth hormone releasing hormone.

          Acromegaly secondary to extra-pituitary tumors secreting growth hormone releasing hormone (GHRH) is rarely encountered. We review the literature on ectopic acromegaly and present the index report of ectopic acromegaly secondary to GHRH secretion from a mediastinal paraganglioma. Clinical and pathological manifestations and therapeutic management of 99 patients with ectopic acromegaly are reviewed. Acromegaly secondary to ectopic GHRH secretion is usually caused by a neuroendocrine tumor in the lung and pancreas. We report an additional cause of ectopic acromegaly from a mediastinal paraganglioma. Diagnostic criteria of ectopic GHRH syndrome include biochemical and pathologic tumoral confirmation of GHRH secretion and expression. Management of ectopic acromegaly consists of surgical resection of the primary tumor and biochemical normalization, with possible adjuvant use of somatostatin analogs. The review demonstrates that there are several tumor types, including paragangliomas which may secrete GHRH, leading to acromegaly. Clinical and laboratory manifestations of the syndrome and challenges in diagnosis and management of these rarely encountered patients require early diagnosis and appropriate treatment to prevent long-term morbidity and mortality with ectopic acromegaly.
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            Clinical characteristics and outcome of acromegaly induced by ectopic secretion of growth hormone-releasing hormone (GHRH): a French nationwide series of 21 cases.

            Ectopic GHRH secretion is a rare cause of acromegaly, and case reports are mainly isolated. From the registry of the sole laboratory performing plasma GHRH assays in France, we identified cases of ectopic GHRH secretion presenting with acromegaly between 1983 and 2008. Twenty-one patients aged 14-77 yr were identified from 12 French hospitals. Median GHRH was 548 (270-9779) ng/liter. Outcome measures included description of tumor features and outcome and the relation between plasma GHRH values and tumor site, size, and spread. The primary neuroendocrine tumor was identified for 20 of 21 patients (12 pancreatic, seven bronchial, one appendicular). Tumors were large (10-80 mm), identified on computed tomography scan in 18 cases and by endoscopic ultrasound and somatostatin receptor scintigraphy in two. Somatostatin receptor scintigraphy had a similar sensitivity to computed tomography scan (81 vs. 86%). Tumors were all well differentiated; 47.6% had metastasized at the time of diagnosis of acromegaly. After a median follow-up of 5 yr, 85% of patients were alive. Ninety-one percent of patients whose tumor was completely removed were considered in remission, and most had normalized plasma GHRH. The remaining patients were treated with somatostatin analogs: IGF-I normalized except for one patient who required pegvisomant, but GHRH levels remained elevated. No correlations were found between GHRH levels and tumor site or size or the existence of metastases. Identification of increased plasma GHRH during follow-up was an accurate indicator of recurrence. The prognosis of endocrine tumors responsible for GHRH secretion appears relatively good. Plasma GHRH assay is an accurate tool for diagnosis and follow-up.
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              Calcitonin-secreting pancreatic neuroendocrine tumors: a case report and review of the literature.

              We report the presentation and novel therapy of a calcitonin-secreting pancreatic neuroendocrine tumor (PNET) and review the literature on this unusual neoplasm.

                Author and article information

                Endocrinol Diabetes Metab Case Rep
                Endocrinol Diabetes Metab Case Rep
                EDM Case Reports
                Endocrinology, Diabetes & Metabolism Case Reports
                Bioscientifica Ltd (Bristol )
                5 February 2016
                : 2016
                : 150134
                [1 ]Endocrinology, Diabetes and Metabolic Unit, Kaplan Medical Center, Hebrew University Medical School of Jerusalem , Bilu 176100, Rehovot, Israel
                [2 ]Institute of Endocrinology and Felsenstein Medical Research Center, Rabin Medical Center , Petach Tikva, 49100, Israel
                [3 ]Sackler School of Medicine, Tel-Aviv University , Tel Aviv, 69978, Israel
                [4 ]Laboratoire d'Hormonologie – CBPE, Hospices Civils de Lyon , 59 bd Pinel69677, Bron Cedex, France
                Author notes
                Correspondence should be addressed to T Zornitzki Email: taiba_z@ 123456clalit.org.il
                © 2016 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

                : 26 January 2016
                : 5 February 2016
                Novel Diagnostic Procedure


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