Abstract
Objective
In MRI-negative cases Cushing’s disease (CD), surgeons perform a more extensive exploration of the pituitary gland, with fewer instances of hormonal remission. 18F-fluoro-deoxy-glucose (18F-FDG) positron emission tomography (PET) has a limited role in detecting adenomas that cause CD (corticotropinomas). Our previous work demonstrated corticotropin-releasing hormone (CRH) stimulation leads to delayed, selective glucose uptake in corticotropinomas. Here, we prospectively evaluated the utility of CRH stimulation in improving 18F-FDG-PET detection of adenomas in CD.
Methods
Subjects with a likely diagnosis of CD (n = 27, 20 females) each underwent two 18F-FDG-PET studies [without and with ovine-CRH (oCRH) stimulation] on a high-resolution PET platform. Standardized-uptake-values (SUV) in the sella were calculated. Two blinded neuroradiologists independently read 18F-FDG-PET images qualitatively. Adenomas were histopathologically confirmed, analyzed for mutations in the USP8 gene and for glycolytic pathway proteins.
Results
The mean-SUV of adenomas was significantly increased from baseline (3.6 ± 1.5) with oCRH administration (3.9 ± 1.7; one-tailed p = 0.003). Neuroradiologists agreed that adenomas were visible on 21 scans, not visible on 26 scans (disagreed about 7, kappa = 0.7). oCRH-stimulation led to the detection of additional adenomas (n = 6) not visible on baseline-PET study. Of the MRI-negative adenomas (n = 5), two were detected on PET imaging (one only after oCRH-stimulation). USP8 mutations or glycolytic pathway proteins were not associated with SUV in corticotropinomas.
Conclusions
The results of the current study suggest that oCRH-stimulation may lead to increased 18F-FDG uptake, and increased rate of detection of corticotropinomas in CD. These results also suggest that some MRI invisible adenomas may be detectable by oCRH-stimulated FDG-PET imaging.
Clinical trial information
18F-FDG-PET imaging with and without CRH stimulation was performed under the clinical trial NIH ID 12-N-0007 (clinicaltrials.gov identifier NCT01459237). The transsphenoidal surgeries and post-operative care was performed under the clinical trial NIH ID 03-N-0164 (clinicaltrials.gov identifier NCT00060541).
Similar content being viewed by others
References
D. Bochicchio, M. Losa, M. Buchfelder, Factors influencing the immediate and late outcome of Cushing’s disease treated by transsphenoidal surgery: a retrospective study by the European Cushing’s Disease Survey Group. J. Clin. Endocrinol. Metab. 80, 3114–3120 (1995)
T. Moshang, Editorial: Cushing’s disease, 70 years later… and the beat goes on. J. Clin. Endocrinol. Metab. 88, 31–33 (2003)
P. Chittiboina, B.K. Montgomery, C. Millo, P. Herscovitch, R.R. Lonser, High-resolution 18 F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging for pituitary adenoma detection in Cushing disease. J. Neurosurg. 122, 1–7 (2014)
I.N. Chowdhury, N. Sinaii, E.H. Oldfield, N. Patronas, L.K. Nieman, A change in pituitary magnetic resonance imaging protocol detects ACTH-secreting tumours in patients with previously negative results. Clin. Endocrinol. 72, 502–506 (2010)
D.A. Finelli, B. Kaufman, Varied microcirculation of pituitary adenomas at rapid, dynamic, contrast-enhanced MR imaging. Radiology 189, 205–210 (1993)
R. Kasaliwal, S.S. Sankhe, A.R. Lila, S.R. Budyal, V.S. Jagtap, V. Sarathi et al. Volume interpolated 3D-spoiled gradient echo sequence is better than dynamic contrast spin echo sequence for MRI detection of corticotropin secreting pituitary microadenomas. Clin. Endocrinol. 78, 825–830 (2013)
R.R. Lonser, J.J. Wind, L.K. Nieman, R.J. Weil, H.L. DeVroom, E.H. Oldfield, Outcome of surgical treatment of 200 children with Cushing’s disease. J. Clin. Endocrinol. Metab. 98, 892–901 (2013)
W.W. de Herder, P. Uitterlinden, H. Pieterman, H.L. Tanghe, D.J. Kwekkeboom, H.A. Pols et al. Pituitary tumour localization in patients with Cushing’s disease by magnetic resonance imaging. Is there a place for petrosal sinus sampling? Clin. Endocrinol. 40, 87–92 (1994)
E.H. Oldfield, J.L. Doppman, L.K. Nieman, G.P. Chrousos, D.L. Miller, D.A. Katz et al. Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N. Engl. J. Med. 325, 897–905 (1991)
J.J. Wind, R.R. Lonser, L.K. Nieman, H.L. DeVroom, R. Chang, E.H. Oldfield, The lateralization accuracy of inferior petrosal sinus sampling in 501 patients with Cushing’s disease. J. Clin. Endocrinol. Metab. 98, 2285–93 (2013)
J. Jagannathan, R. Smith, H.L. DeVroom, A.O. Vortmeyer, C.A.Stratakis, L.K. Nieman, et al. Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease. J. Neurosurg. 111, 531–9 (2009).
E.H. Oldfield, Surgical management of Cushing’s disease: a personal perspective. Clin. Neurosurg. 58, 13–26 (2011)
E.H. Oldfield, A.O. Vortmeyer, Development of a histological pseudocapsule and its use as a surgical capsule in the excision of pituitary tumors. J. Neurosurg. 104, 7–19 (2006)
M. Bergström, C. Muhr, K. Ericson, H. Lundqvist, A. Lilja, L. Eriksson et al. The normal pituitary examined with positron emission tomography and (methyl-11C)-L-methionine and (methyl-11C)-D-methionine. Neuroradiology 29, 221–225 (1987)
B. De Souza, A. Brunetti, M.J. Fulham, R.A. Brooks, D. DeMichele, P. Cook et al. Pituitary microadenomas: a PET study. Radiology 177, 39–44 (1990)
S.H. Hyun, J.Y. Choi, K.-H. Lee, Y.S. Choe, B.-T. Kim, Incidental focal 18F-FDG uptake in the pituitary gland: clinical significance and differential diagnostic criteria. J. Nucl. Med. 52, 547–50 (2011)
S.Y. Jeong, S.-W. Lee, H.J. Lee, S. Kang, J.-H. Seo, K.A. Chun et al. Incidental pituitary uptake on whole-body 18F-FDG PET/CT: a multicentre study. Eur. J. Nucl. Med. Mol. Imaging 37, 2334–43 (2010)
H. Ju, J. Zhou, Y. Pan, J. Lv, Y. Zhang, Evaluation of pituitary uptake incidentally identified on 18F-FDG PET/CT scan. Oncotarget 8, 55544–55549 (2017)
C.W. Koo, P. Bhargava, V. Rajagopalan, M. Ghesani, H. Sims-Childs, N.J. Kagetsu, Incidental detection of clinically occult pituitary adenoma on whole-body FDG PET imaging. Clin. Nucl. Med. 31, 42–3 (2006)
A.S. Alzahrani, R. Farhat, A. Al-Arifi, N. Al-Kahtani, I. Kanaan, M. Abouzied, The diagnostic value of fused positron emission tomography/computed tomography in the localization of adrenocorticotropin-secreting pituitary adenoma in Cushing’s disease. Pituitary 12, 309–14 (2009)
J. Lu, B.K. Montgomery, G.P. Chatain, A. Bugarini, Q. Zhang, X. Wang et al. Corticotropin releasing hormone can selectively stimulate glucose uptake in corticotropinoma via glucose transporter 1. Mol. Cell Endocrinol. 470, 1–10 (2017)
L.K. Nieman, B.M.K. Biller, J.W. Findling, J. Newell-Price, M.O. Savage, P.M. Stewart et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 93, 1526–40 (2008)
N. Patronas, N. Bulakbasi, C.A.A. Stratakis, A. Lafferty, E.H.H. Oldfield, J. Doppman et al. Spoiled gradient recalled acquisition in the steady state technique is superior to conventional postcontrast spin echo technique for magnetic resonance imaging detection of adrenocorticotropin-secreting pituitary tumors. J. Clin. Endocrinol. Metab. 88, 1565–1569 (2003)
R.E. Carson, W.C. Barker, J.-S.L.J.-S. Liow, C.A. Johnson, Design of a motion-compensation OSEM list-mode algorithm for resolution-recovery reconstruction for the HRRT. 2003 IEEE NSS/MIC Conf. Rec. 5:3281–3285 (2003)
DHSS/MRC Group on Obesity Research., James WPT (William PT, Waterlow JC (John C: Research on Obesity: A Report of the DHSS/MRC Group. H.M.S.O, 1976
M. Jenkinson, S. Smith, A global optimisation method for robust affine registration of brain images. Med. Image Anal. 5, 143–56 (2001)
B. Bai, J. Bading, P.S. Conti, Tumor quantification in clinical positron emission tomography. Theranostics 3, 787–801 (2013)
G.P. Chatain, N. Patronas, J.G. Smirniotopoulos, M. Piazza, S. Benzo, A. Ray-Chaudhury, et al. Potential utility of FLAIR in MRI-negative Cushing’s disease. J. Neurosurg. 129, 1–9 (2017)
D.G. Altman, Practical Statistics for Medical Research. London: Chapman and Hall (1991)
F. Maher, S.J. Vannucci, I.A. Simpson, Glucose transporter proteins in brain. FASEB J. 8, 1003–1011 (1994)
J.R. Viña, R.B. Page, D.W. Davis, R.A. Hawkins, Aerobic glycolysis by the pituitary gland in vivo. J. Neurochem. 42, 1479–82 (1984)
M.G.Vander Heiden, L.C. Cantley, C.B. Thompson, P. Mammalian, C. Exhibit, Metabolism A: understanding the Warburg Effect: cell proliferation. Science 324, 1029–1034 (2009)
O. Warburg, Injuring of respiration the origin of cancer cells. Science 123, 309–14 (1956)
S. Filetti, G. Damante, D. Foti, Thyrotropin stimulates glucose transport in cultured rat thyroid cells. Endocrinology 120, 2576–81 (1987)
V.M. Harris, S.V. Bendre, F. Gonzalez De Los Santos, A. Fite, A. El-Yaman El-Dandachli, L. Kurenbekova et al. GnRH increases glucose transporter-1 expression and stimulates glucose uptake in the gonadotroph. J. Endocrinol. 212, 139–147 (2012)
T.L. Francavilla, R.S. Miletich, D. DeMichele, N.J. Patronas, E.H. Oldfield, B.D. Weintraub et al. Positron emission tomography of pituitary macroadenomas: hormone production and effects of therapies. Neurosurgery 28, 826–833 (1991)
H.P. Patt, V. Lele, A. Lila, T. Bandgar, N. Shah, Utility of hCRH-stimulated (18) F-FDG PET-CT scan in localisation of pituitary microadenoma in Cushing’s disease. J. Med. Imaging Radiat. Oncol. 58, 213 (2014)
Z.-Y. Ma, Z.-J. Song, J.-H. Chen, Y.-F. Wang, S.-Q. Li, L.-F. Zhou et al. Recurrent gain-of-function USP8 mutations in Cushing’s disease. Cell Res. 25, 306–317 (2015)
M. Reincke, S. Sbiera, A. Hayakawa, M. Theodoropoulou, A. Osswald, F. Beuschlein et al. Mutations in the deubiquitinase gene USP8 cause Cushing’s disease. Nat. Genet. 47, 31–38 (2014)
H.Wa.M. de Jong, F.H.P. van Velden, R.W. Kloet, F.L. Buijs, R. Boellaard, A. Lammertsma, a: Performance evaluation of the ECAT HRRT: an LSO-LYSO double layer high resolution, high sensitivity scanner. Phys. Med. Biol. 52, 1505–26 (2007)
F.H.P. van Velden, R.W. Kloet, B.N.M. van Berckel, F.L. Buijs, G. Luurtsema, A. Lammertsma, et al. HRRT versus HR+ human brain PET studies: an interscanner test-retest study. J. Nucl. Med. 50, 693–702 (2009)
Funding
This work was supported by National Institutes of Health Intramural Grant ZIA NS003150-01 awarded to Prashant Chittiboina. This work was also supported by the Intramural Research Programs of the National Institute of Neurological Diseases and Stroke, National Institutes of Health Clinical Center, the National Institute of Diabetes and Digestive and Kidney Disorders, and Eunice Kennedy Shriver National Institute for Child Health and Human Development, Bethesda, MD. J.B. was supported by the NIH Medical Research Scholars Program, a public–private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH. For a complete list of donors, please visit http://fnih.org/work/ education-training-0/medical-research-scholars-program.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Combined Neuroscience Institutional Review Board of the NIH and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Boyle, J., Patronas, N.J., Smirniotopoulos, J. et al. CRH stimulation improves 18F-FDG-PET detection of pituitary adenomas in Cushing’s disease. Endocrine 65, 155–165 (2019). https://doi.org/10.1007/s12020-019-01944-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-019-01944-7