Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion from a Meckel diverticulum neuroendocrine tumor: case report
- Diana Loreta Paun†1, 2,
- Lavinia Vija†1Email author,
- Emilia Stan3,
- Alexandra Banica1,
- Elena Bobeica1,
- Dana Terzea1,
- Catalina Poiana1, 2,
- Corin Badiu1, 2 and
- Sorin Paun2, 4
© Paun et al. 2015
Received: 5 March 2015
Accepted: 17 November 2015
Published: 26 November 2015
Ectopic production of adrenocorticotropic hormone (ACTH) by neuroendocrine tumours (NET) is a rare condition, occult presentations often hampering the diagnosis. Although NET are relatively frequent in the ileon and Meckel diverticulum, we describe the first Cushing’s syndrome due to ectopic adrenocorticotropic syndrome (CS-EAS) arising from a Meckel diverticulum.
A 44-year-old man was admitted with recent onset of diabetes, myopathy, edema and hypokalemic metabolic alkalosis consistent with Cushing’s syndrome. Both basal and dynamic laboratory evaluation suggested CS-EAS. Laboratory testing also showed high serum levels of chromogranin A (CgA) and urinary 5-hydroxyindoleacetic acid (5HIAA). Pituitary and neck/thorax/abdomen/pelvis imaging proved to be normal, while somatostatin analogue (99mTc-HYNIC-TOC) scintigraphy revealed increased focalized ileum uptake on the right iliac fossa. Pre-operative ketoconazole and sandostatin treatment controlled the hypercortisolism within a month. Pathological analysis of the resected submucosal 1.8 cm tumour of the Meckel diverticulum and a metastatic local lymph node confirmed a well differentiated neuroendocrine tumour (grade I), whereas immunohistochemistry was positive for ACTH, chromogranin A and synaptophysin. Post-operative clinical and biochemical resolution of Cushing’s syndrome was followed by normalization of both CgA and 5HIAA, which were maintained at the 6 month follow-up.
The identification, characterization and follow-up of this rare cause of ectopic ACTH secretion is important in order to assess the long-term prognostic and management.
KeywordsEctopic Cushing’s syndrome Ectopic ACTH secretion Meckel diverticulum Neuroendocrine tumor Hipokalaemia
Cushing syndrome (CS), secondary to ectopic adrenocorticotropic hormone secretion (CS-EAS), was reported initially in 1928, while the link between CS and a nonpituitary tumor as a source of EAS was established in 1962 , was recently estimated to constitute up to 18 % of all causes of CS [2–8].
Among the variety of tumours, mostly of neuroendocrine origin, associated with CS-EAS [2–4, 7, 8], gastroenteropancreatic tumors (GEP NET) represent 9–17 % [2, 3, 5, 9, 10]. Whereas NET arising from Meckel diverticulum are very rare (more than 120 cases described in the literature [11–15], harbouring particular features among ileal neuroendocrine tumours, from our knowledge, CS-EAS from a Meckel diverticulum was not previously described.
We present the first case of an ectopic adrenocorticotropic hormone secretion, from a Meckel diverticulum neuroendocrine tumor.
A 44-year-old Caucasian man was admitted in June 2014 to the hospital with recent (5 months) onset of ankle oedema, high blood glucose and low potassium levels (1.9 mmol/L). Physical examination showed centripetal distribution of the fat tissue with 10 kg (15 %) weight loss (BMI 25 kg/m2) over 5 months, moon face, buffalo hump, facial rash, dispersed small bruises on the trunk, generalized muscle weakness and muscle hypotrophy of the lower limbs. The remaining physical examination was normal, including blood pressure levels.
Reference range, Adults
Plasma cortisol After 1 mg DXM O/N
After 8 mg 2-d DXM test
24 h-urinary cortisol
58–403 μg/24 h
After 8 mg 2-d DXM test
58–403 μg/24 h
1–10 mg/24 h
The high-dose dexamethasone suppression test (2 mg of dexamethasone every 6 h during 48 h starting at 8 a.m.) showed no cortisol suppression confirming the CS-EAS diagnosis (Table 1). Tumour markers determination showed increased levels of CgA, neuronal specific enolase (NSE), serotonin and 5-hydroxyindoleacetic acid (5-HIAA) (Table 1), all reinforcing an EAS.
The osteodensitometry showed vertebral osteoporosis with a T-score of −2.9 and Z-score of −2.6, consistent with secondary osteoporosis.
Neuroendocrine tumors in Meckel’s diverticulum resemble to ileal NET in their biological behavior more than to appendiceal NET. It was recently reported that 77 % of Meckel diverticulum tumors present histological characteristics for a neuroendocrine origin, but when compared to ileal tumors, the risk of cancer in the Meckel diverticulum was 70 times higher than any other ileal site . In a review of 104 Meckel’s cases of NET, Nies et al.  found an incidence 2.5 greater in men, a frequent localization on the tip of the diverticulum and an exceptional association with metastatic carcinoid syndrome of less than 2 cm. The presented case had a less than 2 cm well differentiated NET with local lymph node extension. Jejuno-ileal NET represent 30–50 % of all small bowel neoplasms, with 72 % survival rates at 5 years for tumours with loco-regional spread [14, 18]. Along with this line, we expect that our patient might follow the same clinical course, or even better, as the histological type corresponded to a well differentiated tumor G1 with Ki67 < 1 %.
Ectopic ACTH syndrome produced by a NET from the gastrointestinal tract is extremely rare and only described in isolated case reports. While only five cases of CS-EAS form appendicular NET were reported in the literature [2, 19–22], from our knowledge we present the first case of CS-EAS from a Meckel diverticulum well differentiated NET.
Clinical features of ectopic ACTH syndrome depend on the source of production and rate of ACTH synthesis. Characteristically, these patients have severe hypercortisolemia leading to low serum potassium levels, diabetes, generalized infections, hypertension, and psychosis. Whether rapidly growing tumours, such as small cell lung cancer typically produce profound and sudden onset of symptoms, well defined Cushingoid body habitus changes are noticed in slower growing tumours such as jejuno-ileal NET, as was demonstrated in this patient.
The current case is the first report of a Meckel diverticulum NET-producing ACTH presenting clinically as Cushing’s syndrome. The diagnosis was assisted by a positive somatostatin analogue whole body scintigraphy.
Localization of EAS tumours is often challenging as occult tumours have been described in 12–19 % of adult patients [2–5, 23]. Modern cross-sectional imaging (CT and/or MRI of the neck/thorax/abdomen/pelvis) are recommended as first line investigations . When these are negative, functional imaging techniques in adults (somatostatin analogues scintigraphy, coupled with SPECT/CT,18F-DOPA-PET-CT or 68Ga-labelled peptides-PET-CT) brought promising results in the localization of jejuno-ileal NET [23, 25, 26].
There have been described only two cases of Meckel diverticulum carcinoma with uptake of FDOPA-PET, FDG-PET and somatostatin receptor scintigraphy .
Metabolic PET scanning using 18-fluorodeoxyglucose (FDG) was not usually recommended since it has a low sensitivity for jejuno-ileal NET, due to low metabolic activity in G1 tumors. Indeed, the sensitivity of CT and combined somatostatin analogues scintigraphy in the localization CS-EAS was found to be higher (53 %) than that of MRI (37 %) or FDG-PET (35 %) .
In the presented case, the somatostatin analogue scintigraphy allowed the localization of the EAS tumour source. Surgical resection was the definitive and optimal management of this rare condition and led to a complete resolution of symptoms.
Further studies on more cases would be needed in order to evaluate the best follow-up procedure, as well as the long term progression free survival and outcome for patients with this rare localization of ileal neuro-endocrine tumor.
Written informed consent was obtained from the patient. A copy of the written consents is available upon request for review by the Journal Editor.
The authors thank doctor Mirela Gherghe from the Nuclear Medicine Department of the Bucharest Oncology Institute, for having provided us with the scintigraphy images, as well as doctors Ana Maria Stefanescu from National Institute of Pathology and Valentin Enache from the Pathology Department of Floreasca Clinical Emmergency Hospital, for their expertise in pathology and for providing us the photographs of both histology and immuno-histochemistry.
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- Meador CK, Liddle GW, Island DP, Nicholson WE, Lucas CP, Nuckton JG, et al. Cause of Cushing’s syndrome in patients with tumors arising from “nonendocrine” tissue. J Clin Endocrinol Metab. 1962;22:693–703.View ArticlePubMedGoogle Scholar
- Ejaz S, Vassilopoulou-Sellin R, Busaidy NL, Hu MI, Waguespack SG, Jimenez C, et al. Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion: the University of Texas MD Anderson Cancer Center Experience. Cancer. 2011;117(19):4381–89.View ArticlePubMedPubMed CentralGoogle Scholar
- Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK. Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005;90(8):4955–62.View ArticlePubMedGoogle Scholar
- Isidori AM, Kaltsas GA, Grossman AB. Ectopic ACTH syndrome. Front Horm Res. 2006;35:143–56.View ArticlePubMedGoogle Scholar
- Isidori AM, Kaltsas GA, Pozza C, Frajese V, Newell-Price J, Reznek RH, et al. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metab. 2006;91(2):371–7.View ArticlePubMedGoogle Scholar
- Salgado LR, Fragoso MC, Knoepfelmacher M, Machado MC, Domenice S, Pereira MA, et al. Ectopic ACTH syndrome: our experience with 25 cases. Eur J Endocrinol. 2006;155(5):725–33.View ArticlePubMedGoogle Scholar
- Wajchenberg BL, Mendonca BB, Liberman B, Pereira MA, Carneiro PC, Wakamatsu A, et al. Ectopic adrenocorticotropic hormone syndrome. Endocr Rev. 1994;15(6):752–87.PubMedGoogle Scholar
- More J, Young J, Reznik Y, Raverot G, Borson-Chazot F, Rohmer V, et al. Ectopic ACTH syndrome in children and adolescents. J Clin Endocrinol Metab. 2011;96(5):1213–22.View ArticlePubMedGoogle Scholar
- Aniszewski JP, Young Jr WF, Thompson GB, Grant CS, van Heerden JA. Cushing syndrome due to ectopic adrenocorticotropic hormone secretion. World J Surg. 2001;25(7):934–40.View ArticlePubMedGoogle Scholar
- Liddle GW, Nicholson WE, Island DP, Orth DN, Abe K, Lowder SC. Clinical and laboratory studies of ectopic humoral syndromes. Recent Prog Horm Res. 1969;25:283–314.PubMedGoogle Scholar
- Anderson DJ. Carcinoid tumor in Meckel’s diverticulum: laparoscopic treatment and review of the literature. J Am Osteopath Assoc. 2000;100(7):432–4.PubMedGoogle Scholar
- Lorenzen AW, O'Dorisio TM, Howe JR. Neuroendocrine tumors arising in Meckel's diverticula: frequency of advanced disease warrants aggressive management. J Gastrointest Surg. 2013;17(6):1084–91.View ArticlePubMedPubMed CentralGoogle Scholar
- Nies C, Zielke A, Hasse C, Ruschoff J, Rothmund M. Carcinoid tumors of Meckel’s diverticula. Report of two cases and review of the literature. Dis Colon Rectum. 1992;35(6):589–96.View ArticlePubMedGoogle Scholar
- Pape UF, Perren A, Niederle B, Gross D, Gress T, Costa F, et al. ENETS Consensus Guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas. Neuroendocrinology. 2012;95(2):135–56.View ArticlePubMedGoogle Scholar
- Poncet G, Hervieu V, Walter T, Lepinasse F, Chardon L, Pilleul F, et al. Neuroendocrine tumors of Meckel's diverticulum: lessons from a single institution study of eight cases. J Gastrointest Surg. 2011;15(1):101–9.View ArticlePubMedGoogle Scholar
- Artiko V, Sobic-Saranovic D, Pavlovic S, Petrovic M, Zuvela M, Antic A, et al. The clinical value of scintigraphy of neuroendocrine tumors using (99m)Tc-HYNIC-TOC. J Buon. 2012;17(3):537–42.PubMedGoogle Scholar
- Thirunavukarasu P, Sathaiah M, Sukumar S, Bartels CJ, Zeh H III, Lee KK, et al. Meckel's diverticulum--a high-risk region for malignancy in the ileum. Insights from a population-based epidemiological study and implications in surgical management. Ann Surg. 2011;253(2):223–30.View ArticlePubMedPubMed CentralGoogle Scholar
- Scherubl H, Jensen RT, Cadiot G, Stolzel U, Kloppel G. Neuroendocrine tumors of the small bowels are on the rise: Early aspects and management. World J Gastrointest Endosc. 2010;2(10):325–34.View ArticlePubMedPubMed CentralGoogle Scholar
- Beddy D, Larson D. Cushing's syndrome cured by resection of an appendiceal carcinoid tumor. Int J Colorectal Dis. 2011;26(7):949–50.View ArticlePubMedGoogle Scholar
- Dobnig H, Stepan V, Leb G, Wolf G, Buchfelder M, Krejs GJ. Recovery from severe osteoporosis following cure from ectopic ACTH syndrome caused by an appendix carcinoid. J Intern Med. 1996;239(4):365–9.View ArticlePubMedGoogle Scholar
- Miller T, Bernstein J, Van Herle A. Cushing’s syndrome cured resection of appendiceal carcinoid. Arch Surg. 1971;103(6):770–3.View ArticlePubMedGoogle Scholar
- Perakakis N, Laubner K, Keck T, Steffl D, Lausch M, Meyer PT, et al. Ectopic ACTH-syndrome due to a neuroendocrine tumour of the appendix. Exp Clin Endocrinol Diabetes. 2011;119(9):525–29.View ArticlePubMedGoogle Scholar
- Tabarin A, Valli N, Chanson P, Bachelot Y, Rohmer V, Bex-Bachellerie V, et al. Usefulness of somatostatin receptor scintigraphy in patients with occult ectopic adrenocorticotropin syndrome. J Clin Endocrinol Metab. 1999;84(4):1193–202.View ArticlePubMedGoogle Scholar
- Zemskova MS, Gundabolu B, Sinaii N, Chen CC, Carrasquillo JA, Whatley M, et al. Utility of various functional and anatomic imaging modalities for detection of ectopic adrenocorticotropin-secreting tumors. J Clin Endocrinol Metab. 2010;95(3):1207–19.View ArticlePubMedPubMed CentralGoogle Scholar
- Balogova S, Talbot JN, Nataf V, Michaud L, Huchet V, Kerrou K, et al. 18F-fluorodihydroxyphenylalanine vs other radiopharmaceuticals for imaging neuroendocrine tumours according to their type. Eur J Nucl Med Mol Imaging. 2013;40(6):943–66.View ArticlePubMedPubMed CentralGoogle Scholar
- Talbot JN, Kerrou K, Missoum F, Grahek D, Aide N, Lumbroso J, et al. 6-[F-18]fluoro-L-DOPA positron emission tomography in the imaging of Merkel cell carcinoma: preliminary report of three cases with 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography or pentetreotide-(111In) SPECT data. Mol Imaging Biol. 2005;7(4):257–61.View ArticlePubMedGoogle Scholar
- Pacak K, Ilias I, Chen CC, Carrasquillo JA, Whatley M, Nieman LK. The role of [(18)F]fluorodeoxyglucose positron emission tomography and [(111)In]-diethylenetriaminepentaacetate-D-Phe-pentetreotide scintigraphy in the localization of ectopic adrenocorticotropin-secreting tumors causing Cushing’s syndrome. J Clin Endocrinol Metab. 2004;89(5):2214–21.View ArticlePubMedGoogle Scholar