Cushings Syndrome Secondary to a Thymic Carcinoid Tumor Due to Multiple Endocrine Neoplasia Type 1

Journal Article

	Cushing's Syndrome Secondary to a Thymic Carcinoid Tumor Due to Multiple Endocrine Neoplasia Type 1 Journal Endocrine Practice Publisher American Association of Clinical Endocrinologists ISSN 1530-891X (Print) 1934-2403 (Online) Subject Health Services, Medical Sciences and Endocrinology Pages 1-16 DOI 10.4158/EP11038.CRR1 Online Date Friday, May 06, 2011
	Accepted

PDF (2.5 MB)

Authors

Ali A Ghazi, MD¹, Azizollah Abbasi Dezfooli, MD², Farzaneh Mohamadi, MD², Seyed Vahid Yousefi, MD¹, Alireza Amirbaigloo, MD¹, Siavash Ghazi, MD¹, Marina Pourafkari, MD³, Dan Berney, MD, FRCPath⁴, Sian Ellard, PhD⁵, Ashley B. Grossman, MD, FRCP, FMedSci⁶

¹Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
²Departments of Thoracic Surgery and Pathology, Masih Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
³Department of Radiology, Taleghani General Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
⁴Consultant Histopathologists, Barts and the London NHS Trust, London, United Kingdom
⁵Consultants Molecular Geneticist, Royal Devon & Exeter NHS Foundation Trust, Exeter, London, United Kingdom
⁶William Harvey Research Institute, Barts, London School of Medicine, London, United Kingdom

Abstract

Objective: To present an Iranian patient who had a non-classic form of MEN1 and presented with ectopic Cushing's syndrome (CS) secondary to an ACTH-producing thymic neuroendocrine tumor (NET), recurrent renal stones and a giant cell granuloma of the jaw, due to primary hyperparathyroidism (PHPT), without involvement of the pituitary or pancreas.

Methods: Relevant imaging and hormonal evaluations were performed. The patient was operated on 2 occasions for a thymic NET and on 3 occasions for PHPT. DNA from a peripheral blood sample was extracted for sequencing of the MEN1 gene.

Result: Histopathologic evaluation of thymic tumor showed atypical carcinoid tumor at first surgery with a Ki-67 of 5% and an invasive carcinoid tumor, with a Ki-67 of 30% at second surgery. Parathyroid pathology was in favor of glandular hyperplasia. Menin gene sequencing revealed a novel frame shift mutation "c1642-1648" in exon 10.

Conclusion: This case of MEN1 is unusual because most thymic NETs in MEN1 have been claimed to be non-functional, and secretion of ACTH or other ectopic hormones to rarely occur. In patients presenting with thymic NETs, the possibility of a MEN1 should be considered, especially in the presence of hyperparathyroidism. The case also shows that the behavior of thymic NETs can change with the passage of time from a slow-growing tumor to a highly invasive neoplasia, and that ectopic ACTH can be produced by these tumors in the context of MEN1.

Keywords

Cushings's syndrome, ectopic ACTH, thymic carcinoid, NET, MEN1

Show References

From http://aace.metapress.com/content/q98718277j20h605/

Congenital adrenal hyperplasia (CAH)

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Early diagnosis for early disease/Intervention

Congenital adrenal hyperplasia is a genetic disorder affecting 1:10,000 to 1:15,000 newborns worldwide and the most severe form of the disease can lead to a life-threatening condition during the first weeks of life.  The disease is caused by enzyme defects in the steroid biosynthesis, the most frequent types being 21- and 11a-hydroxylase deficiency. In both of these the17a-OH-progesterone, a precursor for cortisol, is increased which makes its determination a useful screening method for 95% of all of the CAH cases.

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From http://www.perkinelmer.com/Catalog/Category/ID/Congenital%20adrenal%20hyperplasia%20CAH

Gastric inhibitory polypeptide-dependent cortisol hypersecretion--a new cause of Cushing's syndrome.

André Lacroix, M.D., Edouard Bolté, M.D., Johanne Tremblay, Ph.D., John Dupré, M.D., Pierre Poitras, M.D., Hélène Fournier, M.D., Jean Garon, M.D., Dominique Garrel, M.D., Francis Bayard, M.D., Ph.D., Raymond Taillefer, M.D., Richard J. Flanagan, Ph.D., and Pavel Hamet, M.D., Ph.D.

N Engl J Med 1992; 327:974-980October 1, 1992

Abstract

Background.

Corticotropin-independent nodular adrenal hyperplasia is a rare cause of Cushing's syndrome, and the factors responsible for the adrenal hyperplasia are not known.

Full Text of Background....

Methods.

We studied a 48-year-old woman with Cushing's syndrome, nodular adrenal hyperplasia, and undetectable plasma corticotropin concentrations in whom food stimulated cortisol secretion.

Full Text of Methods....

Results.

Cortisol secretion had an inverse diurnal rhythm in this patient, with low-to-normal fasting plasma cortisol concentrations and elevated postprandial cortisol concentrations that could not be suppressed with dexamethasone. The cortisol concentrations increased in response to oral glucose (4-fold increase) and a lipid-rich meal (4.8-fold increase) or a protein-rich meal (2.6-fold increase), but not intravenous glucose. The infusion of somatostatin blunted the plasma cortisol response to oral glucose. Intravenous infusion of gastric inhibitory polypeptide (GIP) for one hour increased the plasma cortisol concentration in the patient but not in four normal subjects. Fasting plasma GIP concentrations in the patient were similar to those in the normal subjects; feeding the patient test meals induced increases in plasma GIP concentrations that paralleled those in plasma cortisol concentrations. Cell suspensions of adrenal tissue from the patient produced more cortisol when stimulated by GIP than when stimulated by corticotropin. In contrast, adrenal cells from normal adults and fetuses or patients with cortisol-producing or aldosterone-producing adenomas responded to corticotropin but not to GIP.

Full Text of Results....

Conclusions.

Nodular adrenal hyperplasia and Cushing's syndrome may be food-dependent as a result of abnormal responsiveness of adrenal cells to physiologic secretion of GIP. "Illicit" (ectopic) expression of GIP receptors on adrenal cells presumably underlies this disorder. (N Engl J Med 1992;327:974–80.)

Full Text of Conclusions....

Read the Full Article...

Media in This Article

Figure 1Plasma Cortisol Concentrations in a Patient with Food-Induced Cushing's Syndrome during Fasting and after Eating.

Figure 2Plasma Cortisol and GIP Responses to Oral Glucose Administration (○), Intravenous Glucose Administration (●), and Protein-Rich (□) and Lipid-Rich () Meals in a Patient with Food-Induced

Pituitary hyperplasia secondary to acquired hypothyroidism: case report

Roberto Franceschi , Umberto Rozzanigo , Riccarda Failo , Maria Bellizzi and Annunziata Di palma

Italian Journal of Pediatrics 2011, 37:15doi:10.1186/1824-7288-37-15

Published:	7 April 2011

Abstract (provisional)

Objective and Importance: despite recent progress in imaging, it is still difficult to distinguish between pituitary adenoma and hyperplasia, even using Magnetic Resonance Imaging (MRI) with gadolinium injection. We describe an example of reactive pituitary hyperplasia from primary hypothyroidism that mimicked a pituitary macroadenoma in a child.

Clinical Presentation: a 10 year old boy presented with headache and statural growth arrest. MRI revealed an intrasellar and suprasellar pituitary mass. Endocrine evaluation revealed primary hypothyroidism.

Intervention: the patient was started on levothyroxine with resolution of the mass effect.

Conclusion: primary hypothyroidism should be considered in the differential diagnosis of solid mass lesions of the pituitary gland. Examination of thyroid function in patients with sellar and suprasellar masses revealed by MRI may avoid unnecessary operations which can cause irreversible complications.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

From http://www.ijponline.net/content/37/1/15

Hirsutism: Diagnosis and management

doi:10.1016/j.genm.2010.04.002 | How to Cite or Link Using DOI
Copyright © 2010 Excerpta Medica Inc. All rights reserved.

Lindsey Ann Brodell MS^a and Mary Gail Mercurio MD^{, a,}

^a Department of Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, New York

Accepted 2 March 2010. 

Available online 30 April 2010.

Abstract

Background:Hirsutism is defined as excess hair growth in androgen-dependent areas of the body in women.

Objective: This article provides an updated review of hirsutism, focusing on the etiologies, clinical features, approach to diagnostic evaluation, and treatment options.

Methods: The PubMed database was searched for English-language articles published from 1981 to the present, using the terms hirsutism, polycystic ovarian syndrome, congenital adrenal hyperplasia, hirsutism diagnosis, and hirsutism treatment. Reference lists from review articles on hirsutism during this time period were also examined.

Results: While there are many causes of hirsutism, the majority of patients have a benign process that may be idiopathic. In some circumstances, hirsutism is a sign of functional ovarian hyperandrogenism or congenital adrenal hyperplasia. Even more rarely, it is the presenting sign of an internal malignancy.

Conclusions: Hirsutism clinically presents in women as excessive hair growth in androgen-dependent areas. It is a particularly important diagnosis to make, because it often significantly affects a woman's perception of her femininity and less commonly can be a sign of an underlying malignancy or a cutaneous manifestation of a condition with significant cardiovascular or other morbidity. A variety of treatments exist to help minimize the appearance of unwanted hair.

Key words: hirsutism; hypertrichosis; functional ovarian hyperandrogenism; congenital adrenal hyperplasia; hyperandrogenism

Address correspondence to: Mary Gail Mercurio, MD, Department of Dermatology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 697, Rochester, NY 14642.

From http://www.sciencedirect.com

Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia

Author: Andre Lacroix, MD
Section Editor: Lynnette K Nieman, MD
Deputy Editor: Kathryn A Martin, MD

INTRODUCTION

Among the causes of Cushing's syndrome are three rare types of nodular adrenocortical diseases that are usually bilateral:

• Corticotropin (ACTH)-dependent bilateral macronodular hyperplasia secondary to long-term adrenal stimulation in patients with Cushing's disease or ectopic ACTH syndrome
• ACTH-independent micronodular adrenal hyperplasia and its most frequent variant primary pigmented nodular adrenocortical disease (PPNAD), which may be sporadic or familial (as part of the Carney complex)
• ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH)

ACTH-independent bilateral macronodular adrenal hyperplasia will be reviewed here. Other causes of Cushing's syndrome, and primary pigmented nodular adrenocortical disease are discussed separately. (See "Causes and pathophysiology of Cushing's syndrome" and "Cushing's syndrome due to primary pigmented nodular adrenocortical disease".)

CLINICAL FEATURES

ACTH-independent macronodular adrenal hyperplasia (AIMAH) has been described by various terms, including massive macronodular adrenocortical disease (MMAD), autonomous macronodular adrenal hyperplasia (AMAH), ACTH-independent massive bilateral adrenal disease (AIMBAD), and "giant" or "huge" macronodular adrenal disease. AIMAH results in hypercortisolism through a number of mechanisms that are described below. (See 'Pathogenesis' below.)

AIMAH is associated with adrenal glands weighing from 24 to 500 g that contain multiple nonpigmented nodules greater than 5 mm in diameter [1-3]. The nodules appear to be typical benign adrenal nodules, but the internodular cortex may be either hyperplastic or atrophic.

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From http://uptodateonline.com

ClinicalTrialWatch.com's Featured Study: The Seismic Study

The SEISMIC study is a Phase III, multi-center study of Corlux for the treatment of endogenous Cushing's Syndrome.

It is a 6-month study with daily dosing of the investigational drug, Corlux. It is open label, that is, no placebo is required. The protocol includes about 13 clinic visits. After the 6 month treatment period is over, patients return for a 6-week follow up visit.

The study will enroll 50 Cushing's Syndrome patients at approximately 20-25 sites in the US.

The SEISMIC study is seeking patients who require medical treatment for endogenous Cushing's Syndrome due to ectopic ACTH syndrome, adrenal tumors, adrenal hyperplasia, or Cushing's disease when they are not candidates for pituitary surgery or who have failed or recurred after pituitary surgery. Please see detailed eligibility criteria.

See if you are a candidate for this breakthrough Cushing's Syndrome clinical trial

Cushings Articles

Cushing's Syndrome Clinical Trial Qualification Questionnaire

On Dec 05, 2008, Adrian wrote:

The SEISMIC study is seeking patients who require medical treatment for endogenous Cushing's Syndrome due to ectopic ACTH syndrome, adrenal tumors, adrenal hyperplasia, or Cushing's disease when they are not candidates for pituitary surgery or who have failed or recurred after pituitary surgery.

Medical Professionals Interested in Cushing's Syndrome

On Jul 14, 2008, ClinicalTrialWatch Editor wrote:

Medical Professionals: Learn More About The Cushing's Syndrome Clinical Study Study Purpose The SEISMIC Study is a Phase III open label US based clinical research trial designed to test mifepristone in the treatment of the clinical manifestations of endogenous Cushing's ...

SEISMIC Study Eligibility Criteria

On Jul 08, 2008, ClinicalTrialWatch Editor wrote:

SEISMIC Study Main Inclusion Criteria Patients please take the questionnaire Cushing's Syndrome Clinical Trial Qualification Questionnaire to see if you prequalify for the study. Physicians and health care providers view the inclusion and exclusion criteria below and read our ...

Additional Publications and Research

On Jul 07, 2008, ClinicalTrialWatch Editor wrote:

External Publications about Cushing's Syndrome Sartor O, Cutler GB Jr. Mifepristone: treatment of Cushing's syndrome. Clin Obstet Gynecol. 1996 Jun;39(2):50610. Review. http://www.ncbi.nlm.nih.gov/pubmed/8734015?dopt=Abstract Johanssen S, Allolio ...

Friends and Family of Cushing's Syndrome Patients

On Jul 07, 2008, ClinicalTrialWatch Editor wrote:

you know someone suffering with Cushing's Syndrome and believe they may be a candidate for this Phase III clinical trial, please tell them about the SEISMIC Study by sending them a link to the Cushing's Syndrome Clinical Trial Qualification Questionnaire. Please also ...

About Cushing's Syndrome

On Jul 07, 2008, ClinicalTrialWatch Editor wrote:

What is Cushing's Syndrome? Cushing's syndrome was originally described by Harvey Cushing in 1932 and is a relatively rare but serious condition. It is caused by a prolonged exposure to elevated levels of the stress hormone cortisol. Cortisol is produced and released by the adrenal glands; it is necessary for many bodily ...

Articles

ACTH-Independent Cushing's Syndrome with Bilateral Micronodular Adrenal Hyperplasia and Ectopic Adrenocortical Adenoma

Estelle Louiset, Françoise Gobet, Rossella Libé, Anelia Horvath, Sylvie Renouf, Juliette Cariou, Anya Rothenbuhler, Jérôme Bertherat, Eric Clauser, Philippe Grise, Constantine A. Stratakis, Jean-Marc Kuhn, and Hervé Lefebvre*

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 982/Equipe Associée 4310, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (E.L., S.R., J.-M.K., H.L.), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides 23, University of Rouen, 76821 Mont-Saint-Aignan, France; Department of Pathology (F.G.), University Hospital of Rouen, Institute for Biomedical Research, University of Rouen, 76031 Rouen, France; INSERM U567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Assistance Publique-Hôpitaux de Paris, Department of Endocrinology-Metabolism-Cancer (R.L., J.B.), Institut Cochin, Université Paris V-René Descartes, 75014 Paris, France; Section on Endocrinology and Genetics, Program in Developmental Endocrinology and Genetics (A.H., A.R., C.A.S.), National Institute of Child Health & Human Development, Bethesda, Maryland 20892; Oncogenetics Unit (E.C.), Cochin Hospital, 75014 Paris, France; and Departments of Urology (J.C., P.G.) and Endocrinology (J.-M.K., H.L.), University Hospital of Rouen, Institute for Biomedical Research, University of Rouen, 76031 Rouen, France

* To whom correspondence should be addressed. E-mail: herve.lefebvre@chu-rouen.fr.

Context: Bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma are two rare causes of ACTH-independent Cushing's syndrome.

Objective: The aim of the study was to evaluate a 35-yr-old woman with ACTH-independent hypercortisolism associated with both micronodular adrenal hyperplasia and ectopic pararenal adrenocortical adenoma.

Design and Setting: In vivo and in vitro studies were performed in a University Hospital Department and academic research laboratories.

Intervention: Mutations of the PRKAR1A, PDE8B, and PDE11A genes were searched for in leukocytes and adrenocortical tissues. The ability of adrenal and adenoma tissues to synthesize cortisol was investigated by immunohistochemistry, quantitative PCR, and/or cell culture studies.

Main Outcome Measure: Detection of 17{alpha}-hydroxylase and 21-hydroxylase immunoreactivities, quantification of CYP11B1 mRNA in adrenal and adenoma tissues, and measurement of cortisol levels in supernatants by radioimmunological assays were the main outcomes.

Results: Histological examination of the adrenals revealed nonpigmented micronodular cortical hyperplasia associated with relative atrophy of internodular cortex. No genomic and/or somatic adrenal mutations of the PRKAR1A, PDE8B, and PDE11A genes were detected. 17{alpha}-Hydroxylase and 21-hydroxylase immunoreactivities as well as CYP11B1 mRNA were detected in adrenal and adenoma tissues. ACTH and dexamethasone activated cortisol secretion from adenoma cells. The stimulatory action of dexamethasone was mediated by a nongenomic effect involving the protein kinase A pathway.

Conclusion: This case suggests that unknown molecular defects can favor both micronodular adrenal hyperplasia and ectopic adrenocortical adenoma associated with Cushing's syndrome.

From http://jcem.endojournals.org/cgi/content/abstract/jc.2009-0881v1