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      A Case of Pulmonary Carcinoid Tumor with a Superimposed Aspergilloma Presenting As a Covert Ectopic Adrenocorticotropic Hormone Syndrome

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          Abstract

          Ectopic adrenocorticotropic hormone (ACTH) syndrome is a challenging diagnosis only responsible for approximately 10% of Cushing syndrome cases. It has been associated with a variety of benign and malignant tumors including a carcinoid tumor accompanied by aspergilloma in our case that was significantly difficult to be detected. We report a patient over 70 years old with uncontrolled hypertension and hypokalemia presenting with generalized edema. Laboratory results revealed ACTH-dependent Cushing syndrome, but imaging studies did not show any discrete lesions secreting ACTH. The petrosal to peripheral ACTH gradient resulted in no evidence of pituitary adenoma. As the only lesion suspicious for ectopic ACTH secretion was a right lower round cystic lesion that did not appear to be a carcinoid tumor on computed tomography scan of the chest, the patient underwent video-assisted thoracic surgical resection to provide a definitive diagnosis. The final diagnosis was a small ectopic ACTH-secreting carcinoid tumor with unusual superimposed aspergilloma in the periphery of the lung. Postoperatively, the abnormal endocrine levels were normalized, and all of the clinical symptoms and signs were ameliorated. This is an informative case of ectopic ACTH syndrome (EAS) that was the cause of hypokalemia, hypertension, metabolic alkalosis, and hypercortisolism despite its poorly specific cushingoid morphology and uncommon imaging findings. Therefore, we recommend that clinicians investigate any possible lesion as a potential source of EAS.

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          Most cited references18

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          The ectopic ACTH syndrome.

          Ectopic Cushing's syndrome usually relates to the ectopic ACTH syndrome (EAS) and represents ∼20% of ACTH-dependent and ∼10% of all types of Cushing's syndrome (CS). Nearly any neuroendocrine or non-endocrine tumours may be associated with EAS, but the more prevalent tumours are bronchial carcinoids, small cell lung carcinomas, pancreatic carcinoids, thymic carcinoids, medullary carcinomas of the thyroid, and phaeochromocytomas. Occult tumours are highly represented in all the series (12-38%) and constitute the more challenging cases of EAS, requiring long term follow-up. The lack of any completely reliable diagnostic test procedure and imaging to clearly reveal the source of EAS suggests that we should adopt a step-by-step multidisciplinary approach for their diagnosis and therapeutic management. Clinical features are often similar in ACTH-dependent CS, but the rapid onset and progress may suggest an ectopic source. A combination of biochemical tests and imaging studies seems the most appropriate approach for the prompt identification of EAS, even if there are several pitfalls to be avoided along the way. The most appropriate management for cure of EAS, when its source is identified, is surgical excision after controlling the hypercortisolaemia by inhibitors of cortisol secretion and other newer modalities alone or in combination; bilateral adrenalectomy remains an alternative option. Tumour histology, the presence of metastases and the effective control of hypercortisolaemia affect mortality and morbidity. If a source repeatedly fails to be found, the prognosis is often favourable but the identification of a malignant tumour should still be sought during life-long follow-up to avoid the calamity of misdiagnosis.
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            Ectopic ACTH syndrome: our experience with 25 cases.

            Ectopic ACTH syndrome (EAS) occurs in about 5-10% of all patients with ACTH-dependent hypercortisolism with most of them caused by intrathoracic neoplasms. It may be associated with overt malignancies or with occult and indolent tumors. We assessed the accuracy of dynamic tests, inferior petrosal sinus sampling (IPSS) using desmopressin, and imaging in the work-up diagnosis of EAS. Tumor markers, imaging, and outcome data from 25 patients (13F/12M) aged 18-72 years. High dexamethasone suppression test (HDDST), desmopressin test, GHRP-6 test, corticotropin-releasing hormone (CRH) test, IPSS, computed tomography (CT), magnetic resonance imaging (MRI), and (111)In-pentetreotide scintigraphy were revised. In 5 out of 20 patients HDDST was positive. In 13 patients who underwent desmopressin test, ACTH- and cortisol-positive responses were seen in six and five patients respectively. GHRP-6 test was positive in two out of three cases. Two patients underwent CRH test with negative response. In the seven patients submitted to IPSS using desmopressin in six of them, none had ACTH gradients. CT was positive in 15 out of 21 patients and MRI in 8 out of 17 cases. (111)In-pentetreotide scintigraphy was positive in three out of five patients. Fourteen patients had intrathoracic tumors, five had pheochromocytomas, three had pancreatic tumors, one had a glomic tumor, and had three occult tumors. Six out of 11 patients with metastasis died and 3 others without metastasis died. IPSS with desmopressin was helpful for differential diagnosis. Patients initially harboring occult carcinoids may also exhibit severe hypercortisolism and those harboring tymic carcinoids had poor prognoses when compared with bronchial carcinoids and pheocromocytomas.
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              Ectopic ACTH syndrome

              Ectopic adrenocorticotropic secretion (EAS) is responsible for 12-17% of cases of Cushing's syndrome (CS) and covers a range of tumours, from undetectable benign lesions to widespread metastases. The syndrome is often associated with severe hypercortisolaemia, which aggravates the underlying condition. EAS requires a complete workup that includes the establishment of endogenous CS, diagnosis of adrenocorticotropic hormone (ACTH) dependency, localization of the source of ACTH secretion and rapid biochemical control of hypercortisolaemia. Dynamic endocrine tests should include inferior petrosal sinus sampling with CRH stimulation. Localization studies depend on the availability of reliable high-resolution cross-sectional imaging. This systematic review of the largest published series of patients with EAS (over 380 patients) reveals the common trends in the prevalence and management of this syndrome. The concept of 'occult' EAS has been revisited and the terms 'overt' and 'covert' EAS introduced. In addition to small cell lung carcinoma, the most common causes of ectopic EAS are bronchial carcinoids, thymic tumours, islet cell tumour of the pancreas, medullary thyroid carcinomas, and phaeochromocytomas. Their prevalence and the best localization modalities are presented. Medical and surgical management is discussed on the basis of the extensive experience of major referral centres.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                08 June 2017
                2017
                : 8
                : 123
                Affiliations
                [1] 1Division of Endocrinology, Department of Internal Medicine, Korea University College of Medicine , Seoul, South Korea
                [2] 2Department of Pathology, Gil Medical Center, Gachon University , Incheon, South Korea
                [3] 3Department of Pathology, Korea University College of Medicine , Seoul, South Korea
                Author notes

                Edited by: Gabriella Pellegriti, University of Catania, Italy

                Reviewed by: Gianluca Tamagno, Mater Misericordiae University Hospital, Ireland; Matthias Kroiss, University of Würzburg, Germany

                *Correspondence: Ji A Seo, seo-ji-a@ 123456hanmail.net

                Specialty section: This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2017.00123
                5462915
                1f4d0d41-1b1d-46b5-b763-890722283a02
                Copyright © 2017 Kim, Yu, Kim, Kim, Kim and Seo.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 January 2017
                : 22 May 2017
                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 18, Pages: 6, Words: 3719
                Funding
                Funded by: National Research Foundation of Korea 10.13039/501100003725
                Award ID: NRF-2015R1A2A2A01003167
                Categories
                Endocrinology
                Case Report

                Endocrinology & Diabetes
                cushing syndrome,ectopic adrenocorticotropic hormone syndrome,pulmonary carcinoid tumor,aspergilloma,hypercortisolism

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