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      Reversal of a Blunted Follicle-Stimulating Hormone by Chemotherapy in an Inhibin B–Secreting Adrenocortical Carcinoma

      case-report

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          Abstract

          Context:

          Adrenocortical carcinomas (ACCs) are revealed in 60% of cases by steroid hypersecretion. Alternatively, it is uncommon to observe a paraneoplastic syndrome due to a peptide oversecretion.

          Case Description:

          We describe a 60-year-old man with a right adrenal mass. Hormonal evaluation showed an ACTH-independent Cushing syndrome. Surprisingly, follicle-stimulating hormone (FSH) levels were suppressed and blunted during gonadotropin-releasing hormone stimulation, despite normal luteinizing hormone levels. Levels of inhibin B, which negatively regulates the pituitary FSH, were very high. Given the atypical hormonal findings, an adrenal mass biopsy was performed, which allowed the diagnosis of an adrenocortical tumor (positive for steroidogenic factor-1 immunostaining). Moreover, an intense α-inhibin subunit immunostaining was observed. Because of the presence of metastases, the patient received mitotane and chemotherapy (etoposide and cisplatin). After 2 cycles, the inhibin B dropped. After 5 cycles, tumor size was reduced by 15%. Inhibin B levels remained low, and basal and gonadotropin-releasing hormone–stimulated FSH levels normalized. The patient underwent tumor resection, and pathology confirmed the ACC diagnosis (Weiss score of 9). The intensity of the α-inhibin subunit immunostaining was significantly decreased.

          Conclusions:

          We report the case of an inhibin B–secreting ACC in which the response to chemotherapy and mitotane was associated with a normalization of inhibin B secretion, allowing the reversal of the blunted FSH secretion. Inhibin B should be measured in case of suppressed FSH levels despite normal luteinizing hormone levels and may be considered a tumoral marker in some ACCs, even during treatment follow-up.

          Abstract

          Precis: We studied an adrenal mass with suppressed FSH levels, blunted after GnRH stimulation, and found an inhibin B–secreting adrenocortical carcinoma, in which inhibin B was normalized after chemotherapy.

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          Most cited references9

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          Update in adrenocortical carcinoma.

          Adrenocortical carcinoma (ACC) is an orphan malignancy that has attracted increasing attention during the last decade. Here we provide an update on advances in the field since our last review published in this journal in 2006. The Wnt/β-catenin pathway and IGF-2 signaling have been confirmed as frequently altered signaling pathways in ACC, but recent data suggest that they are probably not sufficient for malignant transformation. Thus, major players in the pathogenesis are still unknown. For diagnostic workup, comprehensive hormonal assessment and detailed imaging are required because in most ACCs, evidence for autonomous steroid secretion can be found and computed tomography or magnetic resonance imaging (if necessary, combined with functional imaging) can differentiate benign from malignant adrenocortical tumors. Surgery is potentially curative in localized tumors. Thus, we recommend a complete resection including lymphadenectomy by an expert surgeon. The pathology report should demonstrate the adrenocortical origin of the lesion (eg, by steroidogenic factor 1 staining) and provide Weiss score, resection status, and quantitation of the proliferation marker Ki67 to guide further treatment. Even after complete surgery, recurrence is frequent and adjuvant mitotane treatment improves outcome, but uncertainty exists as to whether all patients benefit from this therapy. In advanced ACC, mitotane is still the standard of care. Based on the FIRM-ACT trial, mitotane plus etoposide, doxorubicin, and cisplatin is now the established first-line cytotoxic therapy. However, most patients will experience progress and require salvage therapies. Thus, new treatment concepts are urgently needed. The ongoing international efforts including comprehensive "-omic approaches" and next-generation sequencing will improve our understanding of the pathogenesis and hopefully lead to better therapies.
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            Clinical features of insulin-like growth factor-II producing non-islet-cell tumor hypoglycemia.

            In some patients with non-islet-cell tumor hypoglycemia (NICTH), a high molecular weight form of IGF-II (big IGF-II) derived from tumors is present in the circulation and might be associated with recurrent hypoglycemia. In this study, in order to survey the clinical characteristics of patients with IGF-II producing NICTH, we analyzed the medical records of 78 patients with NICTH (M/F 44/34, age 62+/-1.8, range; 9-86 years.) whose serum contained a large amount of big IGF-II. Hepatocellular carcinoma and gastric carcinoma were the most common causes of NICTH. The diameters of the tumors were more than 10 cm in 70% of the patients. Basal immunoreactive insulin (IRI) levels were less than 3 microU/dl in 79% of the patients. Hypoglycemic attack was the onset of disease in 31 of 65 cases (48%), but the tumor was revealed prior to the occurrence of hypoglycemia in 34 cases (52%). Twenty-five of 47 (53%) patients had decreased serum potassium levels. These data suggested that hypoinsulinemic hypoglycemia associated with the presence of a large tumor supports the diagnosis of IGF-II producing NICTH. Hypokalemia was associated with hypoglycemia in some patients. The BMI (21.4+/-0.6 kg/m2) and serum total protein levels (6.6+/-0.1g/dl) were preserved at the occurrence of first hypoglycemic attack suggesting that malnutrition might not be the main cause of hypoglycemia in most patients.
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              Activins and inhibins in endocrine and other tumors.

              Inhibin and activin are members of the TGF beta superfamily of growth and differentiation factors. They were first identified as gonadal-derived regulators of pituitary FSH and were subsequently assigned multiple actions in a wide range of tissues. More recently, the inhibin alpha subunit was considered as a tumor suppressor based on functional studies employing transgenic mouse models. This review evaluates the functional and molecular evidence that the inhibin alpha subunit is a tumor suppressor in endocrine cancers. The evaluation highlights the discrepant results from the human and mouse studies, as well as the differences between endocrine tumor types. In addition, we examine the evidence that the activin-signaling pathway is tumor suppressive and identify organ-specific differences in the actions and putative roles of this pathway in endocrine tumors. In summary, there is a considerable body of evidence to support the role of inhibins and activins in endocrine-related tumors. Future studies will define the mechanisms by which inhibins and activins contribute to the process of initiation, promotion, or progression of endocrine-related cancers.
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                Author and article information

                Journal
                J Endocr Soc
                J Endocr Soc
                JS
                JS
                Journal of the Endocrine Society
                Endocrine Society (Washington, DC )
                2472-1972
                01 January 2017
                12 January 2017
                12 January 2017
                : 1
                : 1
                : 46-50
                Affiliations
                Departments of [1 ]Endocrinology,
                [2 ]Hormonology,
                [3 ]Pathology,
                [4 ]Nuclear Medicine, and
                [5 ]Endocrine Surgery, Cochin Hospital, 75014 Paris, France;
                [6 ]Institut National de la Santé et de la Recherche Médicale Unité 982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, France University of Rouen, 76130 Mont-Saint-Aignan, France;
                [7 ]Institut National de la Santé et de la Recherche Médicale Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Université Paris-Descartes, Institut Cochin, 75014 Paris, France; and
                [8 ]French Network for Adrenal Cancer, Cochin Hospital, 75014 Paris, France
                Author notes
                [*]

                These authors contributed equally to this study.

                Address all correspondence to: Rossella Libé, MD, French Network for Adrenal Cancer, Department of Endocrinology, Cochin Hospital, 123 Boulevard Port Royal, 75014 Paris, France. E-mail: rossella.libe@ 123456aphp.fr
                Article
                JS_161009
                10.1210/js.2016-1009
                5677210
                531a8fbc-4d93-47e8-b3ac-ddcfa06409a6
                Copyright © 2017 by the Endocrine Society

                This article has been published under the terms of the Creative Commons Attribution License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 05 October 2016
                : 05 December 2016
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 9, Pages: 5
                Categories
                Case Reports
                Adrenal

                inhibin b,adrenocortical carcinoma,tumor marker
                inhibin b, adrenocortical carcinoma, tumor marker

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