, Volume 22, Issue 5, pp 445–455 | Cite as

Diagnostic utility of Gallium-68-somatostatin receptor PET/CT in ectopic ACTH-secreting tumors: a systematic literature review and single-center clinical experience

  • Elena Varlamov
  • José Miguel Hinojosa-Amaya
  • Madeleine Stack
  • Maria FleseriuEmail author



Tumors causing ectopic Cushing’s syndrome (ECS) are often not visible with conventional imaging. Gallium-68-DOTATATE, DOTATOC, and DOTANOC positron emission tomography/computed tomography (68Ga-SSTR PET/CT) reportedly exhibits greater sensitivity in identifying an ECS source, however, evidence is limited to mainly case reports and a few small retrospective studies. Previous systematic ECS imaging review has shown 68Ga-SSTR PET/CT sensitivity is similar to CT (81.8%) in histologically-proven cases and is 100% in covert-cases, however, the number of patients was small and no occult cases were reported.


We performed a systematic literature review of 68Ga-SSTR PET/CT use in ECS patients. We also report 6 consecutive patients with confirmed active and occult ECS who underwent 68Ga-DOTATATE PET/CT and were followed at our institution between 2014 and 2019.


We identified 33 articles (23 case-reports, 4 case-series, 5 retrospective studies and 1 prospective study) detailing 68Ga-SSTR PET/CT in 69 ECS patients. Overall 68Ga-SSTR PET/CT sensitivity was 64.0%, while in histologically confirmed cases (67 lesions), sensitivity was 76.1%. There were two false-positives cases, both in the adrenal glands. In covert cases, 68Ga-SSTR PET/CT identified 50% of lesions. There were ten occult cases where all imaging failed to identify an adrenocorticotropic hormone source; source remains unknown. In our case series, 68Ga-DOTATATE PET/CT showed decreased uptake in pancreatic neuroendocrine tumor in one patient and did not help identify an ECS source in 5 patients.


Both this systematic literature review, the largest to date, and our single- center experience demonstrate a lower than previously reported 68Ga-SSTR PET/CT sensitivity for ECS, especially in occult lesions. We suggest that the data on 68Ga-SSTR PET/CT in ECS is subject to publication bias, and false-negatives are likely underreported; it’s diagnostic value for ECS needs further study.


Ectopic Cushing’s syndrome Gallium DOTATATE DOTANOC DOTATOC 



The authors thank Shirley McCartney, PhD, for editorial assistance.

Compliance with ethical standards

Conflict of interest

Maria Fleseriu disclosures—Principal Investigator with research funding to OHSU from Novartis, Millendo, Strongbridge and has received occasional scientific consulting fee from Novartis, Strongbridge, and declares no conflict of interest. All other authors declare that they have no disclosures and no conflict of interest

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

The study was institutional review board approved with a waiver of authorization.

Supplementary material

11102_2019_972_MOESM1_ESM.docx (31 kb)
Supplementary material 1 (DOCX 30 kb)


  1. 1.
    Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK (2005) Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab 90(8):4955–4962CrossRefGoogle Scholar
  2. 2.
    Isidori AM, Kaltsas GA, Pozza C, Frajese V, Newell-Price J, Reznek RH, Jenkins PJ, Monson JP, Grossman AB, Besser GM (2006) The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metab 91(2):371–377CrossRefGoogle Scholar
  3. 3.
    Ejaz S, Vassilopoulou-Sellin R, Busaidy NL, Hu MI, Waguespack SG, Jimenez C, Ying AK, Cabanillas M, Abbara M, Habra MA (2011) Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion: the University of Texas MD Anderson Cancer Center experience. Cancer 117(19):4381–4389CrossRefGoogle Scholar
  4. 4.
    Isidori AM, Sbardella E, Zatelli MC, Boschetti M, Vitale G, Colao A, Pivonello R, Group ABCS (2015) Conventional and nuclear medicine imaging in ectopic Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab 100(9):3231–3244CrossRefGoogle Scholar
  5. 5.
    Wannachalee T, Turcu AF, Bancos I, Habra MA, Avram AM, Chuang HH, Waguespack SG, Auchus RJ (2019) The clinical impact of [(68) Ga]-DOTATATE PET/CT for the diagnosis and management of ectopic adrenocorticotropic hormone—secreting tumors. Clin Endocrinol (Oxf). Google Scholar
  6. 6.
    Erickson D, Natt N, Nippoldt T, Young WF Jr, Carpenter PC, Petterson T, Christianson T (2007) Dexamethasone-suppressed corticotropin-releasing hormone stimulation test for diagnosis of mild hypercortisolism. J Clin Endocrinol Metab 92(8):2972–2976CrossRefGoogle Scholar
  7. 7.
    Agzarian J, Quandeel H, Bancos I, Johnson GB, Scharf SC, Thompson GB, Yi JEE, Zhang X, Shen KR (2018) Use of DOTATATE PET/CT scan in the diagnosis and staging of thymic atypical carcinoid tumor in a patient with secondary ACTH-dependent cushing syndrome: look twice and cut once. World J Endocr Surg 10:10127–10133Google Scholar
  8. 8.
    Abubakar S, Amoako YA, Kotze T, Tag N (2017) Source of ectopic acth secretion easily identified by 68Ga DOTANOC PET/CT. Clin Nucl Med 42(4):295–296CrossRefGoogle Scholar
  9. 9.
    Asha HS, Sudeep K, Alexander M, Korula A, Gnanamuthu BR, Thomas N (2011) Cushing’s syndrome in a case of thymic carcinoma. Indian J Endocrinol Metab 15(4):346–348CrossRefGoogle Scholar
  10. 10.
    Balestrieri A, Magnani E, Nuzzo F (2016) Unusual Cushing’s syndrome and hypercalcitoninaemia due to a Small cell prostate carcinoma. Case Rep Endocrinol. Google Scholar
  11. 11.
    Buyukakyuz N, Hillinger S, Weder W, Jungraithmayr W (2017) Bronchopulmonary carcinoid with a single lymph node metastasis causing ectopic Cushing’s syndrome. J Thorac Dis 9(3):E194–E196CrossRefGoogle Scholar
  12. 12.
    Corsello SM, Senes P, Iezzi R, Rufini V, Congedo MT, Paragliola RM, Pontecorvi A (2014) Cushing’s syndrome due to a bronchial ACTH-secreting carcinoid successfully treated with radiofrequency ablation (RFA). J Clin Endocrinol Metab 99(5):E862–E865CrossRefGoogle Scholar
  13. 13.
    Darr R, Zophel K, Eisenhofer G, Abolmaali N, Gastmeier J, Wieczorek K, Jelinek V, Kamvissi V, Bornstein SR, Hofbauer LC (2012) Combined use of 68Ga-DOTATATE and 18F-FDG PET/CT to localize a bronchial carcinoid associated with ectopic ACTH syndrome. J Clin Endocrinol Metab 97(7):2207–2208CrossRefGoogle Scholar
  14. 14.
    Davi MV, Salgarello M, Francia G (2015) Positive (68)Ga-DOTATOC-PET/CT after cortisol level control during ketoconazole treatment in a patient with liver metastases from a pancreatic neuroendocrine tumor and ectopic Cushing syndrome. Endocrine 49(2):566–567CrossRefGoogle Scholar
  15. 15.
    Deldycke A, Haenebalcke C, Taes Y (2018) Paraneoplastic Cushing syndrome, case-series and review of the literature. Acta Clin Belg 73(4):298–304CrossRefGoogle Scholar
  16. 16.
    Dutta R, Kumar A, Julka PK, Mathur SR, Kaushal S, Kumar R, Jindal T, Suri V (2010) Thymic neuroendocrine tumour (carcinoid): clinicopathological features of four patients with different presentation. Interact Cardiovasc Thorac Surg 11(6):732–736CrossRefGoogle Scholar
  17. 17.
    Gabriel S, Garrigue P, Dahan L, Castinetti F, Sebag F, Baumstark K, Archange C, Jha A, Pacak K, Guillet B, Taieb D (2018) Prospective evaluation of (68) Ga-DOTATATE PET/CT in limited disease neuroendocrine tumours and/or elevated serum neuroendocrine biomarkers. Clin Endocrinol (Oxf) 89:155–163CrossRefGoogle Scholar
  18. 18.
    Gani LU, Gianatti EJ, Cheung AS, Jerums G, Macisaac RJ (2011) Failure of functional imaging with gallium-68-DOTA-D-Phe1-Tyr3-octreotide positron emission tomography to localize the site of ectopic adrenocorticotropic hormone secretion: a case report. J Med Case Rep 5:405CrossRefGoogle Scholar
  19. 19.
    Gilardi L, Colandrea M, Fracassi SL, Sansovini M, Paganelli G (2014) (68) Ga- DOTA(0) -Tyr(3) octreotide (DOTATOC) positron emission tomography (PET)/CT in five cases of ectopic adrenocorticotropin-secreting tumours. Clin Endocrinol (Oxf) 81(1):152–153CrossRefGoogle Scholar
  20. 20.
    Goroshi MR, Jadhav SS, Lila AR, Kasaliwal R, Khare S, Yerawar CG, Hira P, Phadke U, Shah H, Lele VR, Malhotra G, Bandgar T, Shah NS (2016) Comparison of 68Ga-DOTANOC PET/CT and contrast-enhanced CT in localisation of tumours in ectopic ACTH syndrome. Endocr Connect 5(2):83–91CrossRefGoogle Scholar
  21. 21.
    Hatipoglu E, Kepicoglu H, Rusen E, Kabasakal L, Gundogdu S, Kadioglu P (2013) Von Hippel Lindau disease with metastatic pancreatic neuroendocrine tumor causing ectopic Cushing’s syndrome. Neuro Endocrinol Lett 34(1):9–13Google Scholar
  22. 22.
    Kakade HR, Kasaliwal R, Jagtap VS, Bukan A, Budyal SR, Khare S, Lila AR, Bandgar T, Menon PS, Shah NS (2013) Ectopic ACTH-secreting syndrome: a single-center experience. Endocr Pract 19(6):1007–1014CrossRefGoogle Scholar
  23. 23.
    Karageorgiadis AS, Papadakis GZ, Biro J, Keil MF, Lyssikatos C, Quezado MM, Merino M, Schrump DS, Kebebew E, Patronas NJ, Hunter MK, Alwazeer MR, Karaviti LP, Balazs AE, Lodish MB, Stratakis CA (2015) Ectopic adrenocorticotropic hormone and corticotropin-releasing hormone co-secreting tumors in children and adolescents causing cushing syndrome: a diagnostic dilemma and how to solve it. J Clin Endocrinol Metab 100(1):141–148CrossRefGoogle Scholar
  24. 24.
    Kasaliwal R, Malhotra G, Lila A, Bandgar T, Shah NS (2015) An unusual case of ectopic ACTH syndrome due to primary retroperitoneal carcinoid. Clin Nucl Med 40(4):364–367CrossRefGoogle Scholar
  25. 25.
    Lococo F, Negro A, Zanelli F, Valli R, Filice A, Rapicetta C, Paci M (2015) Severe Cushing’s syndrome related to a small pulmonary carcinoid with widespread dissemination. Intern Med 54(5):477–480CrossRefGoogle Scholar
  26. 26.
    Ozkan ZG, Kuyumcu S, Balkose D, Ozkan B, Aksakal N, Yilmaz E, Sanli Y, Turkmen C, Aral F, Adalet I (2013) The value of somatostatin receptor imaging with In-111 Octreotide and/or Ga-68 DOTATATE in localizing Ectopic ACTH producing tumors. Mol Imaging Radionucl Ther 22(2):49–55CrossRefGoogle Scholar
  27. 27.
    Papadakis GZ, Bagci U, Sadowski SM, Patronas NJ, Stratakis CA (2015) Ectopic ACTH and CRH co-secreting tumor localized by 68Ga-DOTA-TATE PET/CT. Clin Nucl Med 40(7):576–578CrossRefGoogle Scholar
  28. 28.
    Parihar AS, Mittal BR, Vadi SK, Basher RK, Bhansali A (2018) Ectopic Cushing syndrome (ECS): 68Ga-DOTANOC PET/CT localizes the site of ectopic adrenocorticotropic hormone production. Clin Nucl Med 43(10):769–770Google Scholar
  29. 29.
    Sathyakumar S, Paul TV, Asha HS, Gnanamuthu BR, Paul MJ, Abraham DT, Rajaratnam S, Thomas N (2017) Ectopic Cushing syndrome: a 10-year experience from a tertiary care center in southern india. Endocr Pract 23(8):907–914CrossRefGoogle Scholar
  30. 30.
    Schalin-Jantti C, Ahonen A, Seppanen M (2012) 18F-DOPA PET/CT but not 68Ga-DOTA-TOC PET/CT revealed the underlying cause of ectopic Cushing syndrome. Clin Nucl Med 37(9):904–905CrossRefGoogle Scholar
  31. 31.
    Szajer J, Yung G, Russo R, Mansberg R (2017) Adrenocorticotropic hormone-secreting neuroendocrine tumor of the rectum demonstrated on 68Ga-DOTATATE and 18F-FDG PET imaging. Clin Nucl Med 42(10):773–775CrossRefGoogle Scholar
  32. 32.
    Thomas T, Zender S, Terkamp C, Jaeckel E, Manns MP (2013) Hypercortisolaemia due to ectopic adrenocorticotropic hormone secretion by a nasal paraganglioma: a case report and review of the literature. BMC Res Notes 6:331CrossRefGoogle Scholar
  33. 33.
    Treglia G, Salomone E, Petrone G, Giaccari A, Rindi G, Rufini V (2013) A rare case of ectopic adrenocorticotropic hormone syndrome caused by a metastatic neuroendocrine tumor of the pancreas detected by 68Ga-DOTANOC and 18F-FDG PET/CT. Clin Nucl Med 38(7):e306–e308CrossRefGoogle Scholar
  34. 34.
    Venkitaraman B, Karunanithi S, Kumar A, Bal C, Ammini AC, Kumar R (2014) (6)(8)Ga-DOTATOC PET-CT in the localization of source of ectopic ACTH in patients with ectopic ACTH-dependent Cushing’s syndrome. Clin Imaging 38(2):208–211CrossRefGoogle Scholar
  35. 35.
    Venugopal H, Griffin K, Amer S (2015) A case of severe ectopic ACTH syndrome from an occult primary—diagnostic and management dilemmas. Endocrinol Diabetes Metab Case Rep 2015:150099Google Scholar
  36. 36.
    Verburg FA, Anlauf M, Mottaghy FM, Karges W (2015) Somatostatin receptor imaging-guided pasireotide therapy in medullary thyroid cancer with ectopic adrenocorticotropin production. Clin Nucl Med 40(1):e83–e84CrossRefGoogle Scholar
  37. 37.
    Willhauck MJ, Popperl G, Rachinger W, Giese A, Auernhammer CJ, Spitzweg C (2012) An unusual case of ectopic ACTH syndrome. Exp Clin Endocrinol Diabetes 120(2):63–67CrossRefGoogle Scholar
  38. 38.
    Rufini V, Baum RP, Castaldi P, Treglia G, De Gaetano AM, Carreras C, Kaemmerer D, Hommann M, Horsch D, Bonomo L, Giordano A (2012) Role of PET/CT in the functional imaging of endocrine pancreatic tumors. Abdom Imaging 37(6):1004–1020CrossRefGoogle Scholar
  39. 39.
    Sadowski SM, Neychev V, Millo C, Shih J, Nilubol N, Herscovitch P, Pacak K, Marx SJ, Kebebew E (2016) Prospective study of 68Ga-DOTATATE positron emission tomography/computed tomography for detecting gastro-entero-pancreatic neuroendocrine tumors and unknown primary sites. J Clin Oncol 34(6):588–596CrossRefGoogle Scholar
  40. 40.
    Nakamoto Y, Sano K, Ishimori T, Ueda M, Temma T, Saji H, Togashi K (2015) Additional information gained by positron emission tomography with (68)Ga-DOTATOC for suspected unknown primary or recurrent neuroendocrine tumors. Ann Nucl Med 29(6):512–518CrossRefGoogle Scholar
  41. 41.
    Ambrosini V, Nanni C, Fanti S (2014) The use of gallium-68 labeled somatostatin receptors in PET/CT imaging. PET Clin 9(3):323–329CrossRefGoogle Scholar
  42. 42.
    de Bruin C, Feelders RA, Waaijers AM, van Koetsveld PM, Sprij-Mooij DM, Lamberts SW, Hofland LJ (2009) Differential regulation of human dopamine D2 and somatostatin receptor subtype expression by glucocorticoids in vitro. J Mol Endocrinol 42(1):47–56CrossRefGoogle Scholar
  43. 43.
    de Bruin C, Hofland LJ, Nieman LK, van Koetsveld PM, Waaijers AM, Sprij-Mooij DM, van Essen M, Lamberts SW, de Herder WW, Feelders RA (2012) Mifepristone effects on tumor somatostatin receptor expression in two patients with Cushings syndrome due to ectopic adrenocorticotropin secretion. J Clin Endocrinol Metab 97(2):455–462CrossRefGoogle Scholar
  44. 44.
    Kayani I, Conry BG, Groves AM, Win T, Dickson J, Caplin M, Bomanji JB (2009) A comparison of 68 Ga-DOTATATE and 18F-FDG PET/CT in pulmonary neuroendocrine tumors. J Nucl Med 50(12):1927–1932CrossRefGoogle Scholar
  45. 45.
    Zampetti B, Grossrubatscher E, Dalino Ciaramella P, Boccardi E, Loli P (2016) Bilateral inferior petrosal sinus sampling. Endocr Connect 5(4):R12–R25CrossRefGoogle Scholar
  46. 46.
    Swearingen B, Katznelson L, Miller K, Grinspoon S, Waltman A, Dorer DJ, Klibanski A, Biller BM (2004) Diagnostic errors after inferior petrosal sinus sampling. J Clin Endocrinol Metab 89(8):3752–3763CrossRefGoogle Scholar
  47. 47.
    Sharma ST, Nieman LK (2013) Is prolactin measurement of value during inferior petrosal sinus sampling in patients with adrenocorticotropic hormone-dependent Cushing’s Syndrome? J Endocrinol Invest 36(11):1112–1116Google Scholar
  48. 48.
    Greene LW, Geer EB, Page-Wilson G, Findling JW, Raff H (2019) Assay-Specific Spurious ACTH results lead to misdiagnosis, unnecessary testing, and surgical misadventure—a case series. J Endocr Soc 3(4):763–772CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medicine, Division of Endocrinology, Diabetes and Clinical NutritionOregon Health & Science UniversityPortlandUSA
  2. 2.Department of Neurological SurgeryOregon Health & Science UniversityPortlandUSA
  3. 3.Northwest Pituitary CenterOregon Health & Science UniversityPortlandUSA
  4. 4.Endocrinology Division, Department of Medicine, Hospital Universitario “Dr. José E. González”Universidad Autónoma de Nuevo LeónMonterreyMexico

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